CN101346346B - Amine compound and use thereof for medical purposes - Google Patents

Amine compound and use thereof for medical purposes Download PDF

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CN101346346B
CN101346346B CN2006800472557A CN200680047255A CN101346346B CN 101346346 B CN101346346 B CN 101346346B CN 2006800472557 A CN2006800472557 A CN 2006800472557A CN 200680047255 A CN200680047255 A CN 200680047255A CN 101346346 B CN101346346 B CN 101346346B
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compound
reaction
acid
trifluoromethyl
hours
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CN101346346A (en
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城内正寿
丸川薰
小林信教
菅原邦夫
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Mitsubishi Tanabe Pharma Corp
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Abstract

The invention relates to a novel amine compound represented by the following formula (I), which is superior in immunosuppressive action, rejection suppressive action and the like, and shows reduced side effects such as bradycardia and the like, or a pharmaceutically acceptable acid addition salt thereof, or hydrates thereof, or solvate, as well as a pharmaceutical composition containing this compound and a pharmaceutically acceptable carrier, wherein R is a hydrogen atom or P(-O)(OH)2, X is an oxygen atom or a sulfur atom, Y is CH2CH2 or CH-CH, R1 is cyano or alkyl having a carbon number of 1 to 4 and substituted by a halogen atom(s), R2 is alkyl having a carbon number of 1 to 4 and optionally substituted by a hydroxyl group(s) or a halogen atom(s), R3 and R4 may be the same or different and each is a hydrogen atom or alkyl having a carbon number of 1 to 4, and n is 5-8.

Description

Amine compound and medicinal use thereof
Technical field
The present invention relates to the purposes of a kind of amine compound and conduct medicine thereof.
Background technology
In recent years, such calcineurin (calcineurin) Depressant of cyclonol or FK506 is for the patient's that suppresses to accept organ transplantation immunological rejection and be used.But, can cause deleterious spinoffs such as renal toxicity, liver toxicity, neurotoxicity as certain calcineurin Depressant of 3-methyl cyclohexanol alcohols.Therefore, in order to suppress transplant patient's rejection, further developing safety, medicament that validity is high.
2-aminopropane-1 is disclosed in patent documentation 1～3; The 3-diol compound; It is as the suppressor factor of (acute or chronic) rejection in internal organs or the bone marrow transplantation, or is useful as various auto-immune diseases such as psoriasis, Bei Qiete syndrome and rheumatosis treatment of diseases medicine.
2-amino-the 2-of one of these compounds [2-(4-octyl phenyl) ethyl] propane-1,3-diol hydrochloride (below be also referred to as FTY720) is the clinical compound of developing at present as the suppressor factor of rejection in the renal transplantation.FTY720 in vivo through Sphingosine kinase (sphingosine kinases) change into immediately phosphorylation FTY720 [below be also referred to as FTY720-P.For example can enumerate 2-amino-2-phosphinylidyne oxygen ylmethyl-4-(4-octyl phenyl) butanols].FTY720-P is 4 kinds of S1P acceptor (S1P in 5 kinds of sphingosine-1-phosphates (below be also referred to as S1P) acceptor (following S1P1～5 that are called respectively)
Except 2) in play (non-patent literature 1) of agonist effect.
Recently, the S1P1 that reports in the S1P acceptor being arranged is necessary in the process that from thymus gland and 2 grades of lymphoid tissues, migrates out mature lymphocyte.In non-patent literature 2, having instructed FTY720-P has been the effect of S1P1 agonist, and the S1P1 on the lymphocyte is reduced.The result is hindered from the shifting out of mature lymphocyte of thymus gland and 2 grades of lymphoid tissues, and the circulation mature lymphocyte in the blood is isolated in 2 grades of lymphoid tissues, thus the performance immunosuppressive action.
On the other hand; Present 2-aminopropane-1,3-diol compound worry to have the of short duration bradycardic spinoff of discovery, in order to address this problem; Have a plurality ofly about with 2-aminopropane-1, the 3-diol compound is done the modification of chemical structure and is obtained the report of new compound.In these reports; On the phenyl ring that has at FTY720, add substituent compound; Disclose in the patent documentation 4 as aminopropanol derivatives, disclose aminopropanol derivatives simultaneously in patent documentation 5, the patent documentation 6 as the S1P receptor modulators with S1P receptor modulators of phosphate.But as the substituting group on the phenyl ring, tri haloalkyl, for example trifluoromethyl are not disclosed in them.Present present situation is any level that satisfies as the pharmaceutical products security that still do not reach.
[patent documentation 1] International Publication text WO94/08943 number
[patent documentation 2] International Publication text WO96/06068 number
[patent documentation 3] International Publication text WO98/45429 number
[patent documentation 4] International Publication text WO02/076995 number
[patent documentation 5] International Publication text WO2004/096752 number
[patent documentation 6] International Publication text WO2004/110979 number
[non-patent literature 1] Science, 2002, No. 296,346～349 pages
[non-patent literature 2] Nature, 2004, No. 427,355～360 pages
Summary of the invention
The object of the present invention is to provide a kind of immunosuppressive action, rejection restraining effect etc. good, can alleviate the new amine compound of spinoffs such as bradyrhythmia.
The inventor etc. further study at the laggard row of consideration the problems referred to above, and the amine compound of stating such ad hoc structure formula after result's discovery has can reach its intended purposes, thereby accomplishes the present invention.
That is, main contents of the present invention are as follows.
1, a kind of compound or its pharmaceutically useful acid salt or their hydrate or solvate, it is represented with formula (I).
[Chemical formula 1]
(in the formula, R is Wasserstoffatoms or P (=O) (OH) 2, X is Sauerstoffatom or sulphur atom, Y is CH 2CH 2Or CH=CH, R 1Be to be 1～4 alkyl or cyanic acid by the substituted carbonatoms of halogen atom, R 2Be can be by hydroxyl substituted or can be 1～4 alkyl by the substituted carbonatoms of halogen atom, R 3And R 4Can be identical or different, represent that respectively Wasserstoffatoms or carbonatoms are 1～4 alkyl, n is 5～8.)。
2, like compound or its pharmaceutically useful acid salt or their hydrate or the solvate of record in 1, wherein, R 3And R 4Be Wasserstoffatoms simultaneously.
3, like compound or its pharmaceutically useful acid salt or their hydrate or the solvate of record in 1 or 2,
It is a formula (Ia) or (Ib)
[Chemical formula 2]
Figure S2006800472557D00031
(in the formula, R is hydrogen or P (=O) (OH) 2, X is Sauerstoffatom or sulphur atom, R 1Be to be 1～4 alkyl or cyanic acid by the substituted carbonatoms of halogen atom, R 2Be to replace or be 1～4 alkyl by the substituted carbonatoms of halogen atom by hydroxyl.)
4, like compound or its pharmaceutically useful acid salt or their hydrate or the solvate of record among one of any in 1～3, wherein, X is a Sauerstoffatom.
5, as 1～4 one of any in compound or its pharmaceutically useful acid salt or their hydrate or the solvate of record, wherein, Y is CH 2CH 2
6, like compound or its pharmaceutically useful acid salt or their hydrate or solvate, the wherein R of record among one of any in 1～5 1Be by the substituted methyl of halogen atom.
7, like compound or its pharmaceutically useful acid salt or their hydrate or the solvate of record among one of any in 1～6, wherein, R 1It is trifluoromethyl.
8, like compound or its pharmaceutically useful acid salt or their hydrate or the solvate of record among one of any in 1～7, R 2Be can be by the substituted methyl of hydroxyl.
9, like compound or its pharmaceutically useful acid salt or their hydrate or the solvate of record among one of any in 1～8, R 2It is methylol.
10, like compound or its pharmaceutically useful acid salt or their hydrate or the solvate of record among one of any in 1～9, R is a Wasserstoffatoms.
11, like compound or its pharmaceutically useful acid salt or their hydrate or the solvate of record among one of any in 1～4, the compound of general formula (I) is one of any among following a～e.
A.2-amino-2-[2-(4-oxygen in heptan base-3-trifluoromethyl) ethyl] propane-1,3-glycol or its pharmaceutically useful acid salt or their hydrate or solvate
B. (E)-2-amino-2-[2-(4-oxygen in heptan base-3-trifluoromethyl) vinyl] propane-1,3-glycol or its pharmaceutically useful acid salt or their hydrate or solvate
C.2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-methyl butanol or its pharmaceutically useful acid salt or their hydrate or solvate
D. (R)-2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-methyl butanol or its pharmaceutically useful acid salt or their hydrate or solvate
E.2-amino-2-[2-(3-cyanic acid-4-oxygen in heptan base phenyl) ethyl] propane-1,3-glycol or its pharmaceutically useful acid salt or their hydrate or solvate
12, like compound or its pharmaceutically useful acid salt or their hydrate or the solvate of record among one of any in 1～4, the compound of general formula (I) is any one among following f～j.
F.2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-(phosphinylidyne oxygen ylmethyl) butanols or its pharmaceutically useful acid salt or their hydrate or solvate
G. (E)-2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-(phosphinylidyne oxygen ylmethyl)-3-butene-1-alcohol or its pharmaceutically useful acid salt or their hydrate or solvate
H. mono phosphoric acid ester [2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-methylbutyl] ester or its pharmaceutically useful acid salt or their hydrate or solvate
I. (R)-mono phosphoric acid ester [2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-methylbutyl] ester or its pharmaceutically useful acid salt or their hydrate or solvate
J.2-amino-4-(3-cyanic acid-4-oxygen in heptan base phenyl)-2-(phosphinylidyne oxygen ylmethyl) butanols or its pharmaceutically useful acid salt or their hydrate or solvate
13,2-amino-2-[2-(4-oxygen in heptan base-3-trifluoromethyl) ethyl] propane-1,3-glycol or its hydrochloride.
14, medical composition, it contains one of any compound and pharmaceutically useful carrier in 1～13.
15, like the medical composition of record in 14, in treatment or prevention from immunological disease; Prevention or inhibition to the opposing in the transplanting of organ or tissue or acute rejection or chronic rejection; By the transplant antagonism host (GvH) of bone marrow transplantation sick treatment or prevention; Purposes in allergic disorder treatment or the prevention.
16, like the medical composition of record in 14, be rheumatic arthritis, multiple sclerosis, encephalomyelitis, systemic lupus erythematosus, systemic lupus erythematosus, nephrotic syndrome, chronic eczema, type i diabetes from immunological disease.
17, like the medical composition of record in 14, allergic disorder is specific reaction atopic dermatitis, allergic rhinitis, asthma.
According to the present invention, can provide have good peripheral blood lymphocyte minimizing effect, alleviate the new compound of spinoffs such as bradyrhythmia.
Embodiment
Specify the present invention below.
The compounds of this invention is formula (I)
[chemical formula 3]
Figure S2006800472557D00051
(in the formula, R is Wasserstoffatoms or P (=O) (OH) 2, X is Sauerstoffatom or sulphur atom, Y is CH 2CH 2Or CH=CH, R 1Be to be 1～4 alkyl or cyanic acid by the substituted carbonatoms of halogen atom, R 2Be can be by hydroxyl substituted or can be 1～4 alkyl by the substituted carbonatoms of halogen atom, R 3And R 4Can be identical or different, represent that respectively Wasserstoffatoms or carbonatoms are 1～4 alkyl, n is 5～8.) expression compound or its pharmaceutically useful acid salt or metal-salt or their hydrate or solvate.
Halogen atom is meant fluorine atom, chlorine atom, bromine atoms, iodine atom among the present invention, preferred fluorine atom.
Carbonatoms is that 1～4 alkyl is meant that the carbonatoms of straight or branched is 1～4 alkyl, for example can enumerate methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec.-butyl, the tertiary butyl (represent with t-or tert-by following " 3rd level ".) etc., preferably have methyl, ethyl, n-propyl, sec.-propyl, more preferably methyl, ethyl.
As the preferred example of the R in the above-mentioned general formula (I), can enumerate Wasserstoffatoms.
Preferred example as X can have been enumerated Sauerstoffatom, can enumerate CH as the preferred example of Y 2CH 2
The preferred example of n is 6 or 7, more preferably 6.
As R 1Preferred example methyl fluoride, difluoromethyl, trifluoromethyl, 2,2 are arranged, 2-trifluoroethyl, cyanic acid, more preferably trifluoromethyl, cyanic acid, and then preferred trifluoromethyl.
As R 2Preferred example; Methyl, ethyl, methylol, hydroxyethyl, methyl fluoride, chloromethyl, fluoro ethyl, two fluoro ethyls, trifluoroethyl, three chloroethyls can have been enumerated; More preferably methyl, ethyl, methylol, 2-hydroxyethyl, 2-fluoro ethyl; And then preferable methyl, methylol, most preferably methylol.
As R 3And R 4Preferred example, they can be same to each other or different to each other, and can enumerate Wasserstoffatoms, methyl, ethyl, more preferably Wasserstoffatoms, methyl, most preferably Wasserstoffatoms.
As the pharmaceutically useful acid salt of The compounds of this invention, inorganic acid salt, organic acid salt, an alkali metal salt, alkali earth metal salt etc. can have been enumerated.And, can also comprise in the The compounds of this invention except above-mentioned general formula (I) compound and their geometrical isomer, optically active body, hydrate and the solvate the pharmaceutically useful acid salt thereof.
As the object lesson of The compounds of this invention, the compound that can be listed below.
2-amino-2-{ [2-(4-oxygen in heptan base-3-trifluoromethyl) ethyl] } propane-1,3-glycol or its hydrochloride,
(E)-2-amino-2-[2-(4-oxygen in heptan base-3-trifluoromethyl) vinyl] propane-1,3-glycol or its hydrochloride,
(R)-2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-methyl butanol or its hydrochloride.
In the The compounds of this invention, preferred compound is 2-amino-2-[2-(4-oxygen in heptan base-3-trifluoromethyl) ethyl] propane-1,3-glycol and hydrochloride thereof.
The compound method of The compounds of this invention
Compound method as The compounds of this invention can be enumerated following method.
1) in the The compounds of this invention, the R in the general formula (Ia) is that Wasserstoffatoms, X are Sauerstoffatom, R 1Be to be that the compound (I-1) that 1～4 alkyl is represented comes synthetic through following circuit (II) by the substituted carbonatoms of halogen atom.
[chemical formula 4]
Route 1
Figure S2006800472557D00061
(in the formula, R a, R b, R c, R dThe expression blocking group, X a, X bThe expression leaving group, R 1The substituted carbonatoms of expression halogen atom is 1～4 alkyl, R 2Expression can be 1～4 alkyl by hydroxyl replacement or the substituted carbonatoms of halogen atom.)
R in the formula aSo long as the group of Wasserstoffatoms or protection carboxyl, not special restriction.Alkyl (being specially methyl, ethyl etc.), aralkyl (benzyl etc.) and R for example can have been enumerated bIdentical substituting group etc.R in the formula bSo long as the group of protection phenolic hydroxyl group, not special restriction.Alkyl (being specially methyl, heptyl etc.), aralkyl (benzyl etc.) etc. for example can have been enumerated.As R bWhen using heptyl, without deprotection R bJust can obtain inventing compound (I-1).R in the formula cSo long as the group of protection hydroxyl, not special restriction.For example can enumerate the substituting group (being specially methoxymethyl, THP trtrahydropyranyl etc.) of acyl group (preferred carbonatoms is about 2～4 group, is specially ethanoyl etc.), trialkylsilkl (trimethyl silyl etc. is specifically arranged), benzyl or formation acetal compound.R 2When having hydroxyl, its blocking group R e(as R eSpecifically be and R cThe same group) and R cIn conjunction with, form cyclic acetal and also can.R in the formula dShown blocking group is so long as the amino group of protection, not restriction especially.For example can enumerate acyl group (preferred carbonatoms is about 2～4, is specially ethanoyl etc.), carbamate groups (being specially tert-butoxycarbonyl or benzyloxycarbonyl etc.) etc.And X aShown leaving group is so long as through alkoxide ion (R bThe group of leaving away during-O-) replacement(metathesis)reaction, not special restriction.Halogen atom (being specially fluorine atom etc.), tosyloxy etc. for example can have been enumerated.X bShown leavings group is so long as leave away when midbody (II-4) and triphenylphosphine condensation, so long as do not hinder the group of reaction, not special restriction during the reaction of Wittig below.Halogen atom (being specially iodine atom, bromine atoms, chlorine atom etc.), methanesulfonyloxy group, tosyloxy etc. for example can have been enumerated.
First step is through on 4, having leavings group X aTRIMETHOXY BENZOIC ACID (FOR MANUFACTURING OF T.M. verivate (II-1) and ethanol R bThe condensation of-OH is introduced on 4 has blocking group R bOxygen functional group, obtain the reaction of midbody (II-2).This step can be at N, in the ether series solvents such as dinethylformamide or DMSO 99.8MIN. isopolarity solvent or THF, in the presence of alkali, carries out.Can use mineral alkalis, 1 such as sodium hydride or Pottasium Hydroxide as alkali, 8-azo dicyclo [5.4.0] 11 carbon-organic basess such as 7-alkene carry out.As reaction conditions, enumerated at ice-cold following about～100 ℃ and carried out about 10 minutes～10 hours.Can extract according to usual method after the reaction, clean, dry, remove solvent etc., make with extra care by distillation, silica gel column chromatography, recrystallize etc. as required, obtain title product.
Second step is the carboxyl of reduction midbody (II-2), obtains having the reaction of the midbody (II-3) of hydroxyl.The reagent that in reduction, uses; So long as normally used product; Not special restriction can be enumerated basic metal or boron cpds such as metallic hydrogen coordination compound, diborane such as metal hydrides such as alkaline-earth metal, diisobutylaluminium hydride, lithium aluminum hydride or Peng Qinghuana such as sodium, use the contact hydrogenation of homogeneous phase or heterogeneous catalyzer etc.Reaction conditions can be selected suitable temperature and time according to the original reagent of going back that uses.Concrete, in ether series solvents such as THF, carry out about 10 minutes～12 hours, by diborane, lithium aluminum hydride, lithium borohydride reduction from-30 ℃～reflux temperature; In the mixed solvent of pure series solvent such as ethanol or ether series solvents such as pure series solvent and THF, ice-coldly carry out about 30 minutes～24 hours to reflux temperature down, by Peng Qinghuana or hydroboration calcium reduction etc.Reaction back through usual method stopped reaction, extraction, cleaning, drying, remove and desolvate etc., make with extra care through distillation, silica gel column chromatography, recrystallize etc. as required, obtain title product.
Third step is that the hydroxyl with midbody (II-3) is transformed into leavings group X bReaction.As reagent, so long as can ethanol property hydroxyl be transformed into X bReagent, not special restriction.X bThe reagent that uses during for halogen atom have N-chlorosuccinimide, N-bromosuccinimide, tetracol phenixin or they and reaction auxiliarys such as triphenylphosphine, alkali combination, with hydrochloric acid, Hydrogen bromide, the so-called mineral acid of hydroiodic acid HI, phosphorus tribromide, phosphorus pentabromide, phosphorus trichloride, phosphorus pentachloride, iodine, bromine, chlorine, halo thionyl etc.As reaction conditions, can be set forth in the organic solvent of ether series solvents such as halogen series solvents such as methylene dichloride or THF etc., carrying out about 10 minutes～6 hours under-30 ℃～130 ℃.Also can in two coating systems of organic solvent such as the aqueous solution or toluene and water, react when in addition, using mineral acid.As X bThe reagent that uses during for sulfonyloxy has the chloro alkylsulfonyl of methyl chloride alkylsulfonyl or chlorotoluene alkylsulfonyl etc. and the combination of organic basess such as triethylamine or pyridine.As reaction conditions, can enumerate in the organic solvent of ether series solvents such as halogen series solvents such as methylene dichloride or THF etc., carrying out about 5 minutes～3 hours under-30 ℃～50 ℃.Make with extra care through distillation, silica gel column chromatography, recrystallize etc. through usual method stopped reaction, extraction, cleaning, drying, removal solvent etc. as required the reaction back, can obtain title product.
The 4th step is with having leavings group X bThe reaction of midbody (II-4) and triphenylphosphine, the reaction of Huo De phosphonium salt (II-5).As reaction conditions, can enumerate in inert solvents such as diethyl ether, benzene, toluene, at room temperature～reflux temperature carries out about 30 minutes～12 hours.Carry out as required after the reaction solvent heat up in a steamer, cool off, add insoluble solvents such as Di Iso Propyl Ether and hexane after, the solid that leaching is separated out obtains title product.
The 5th step Shi Jiang phosphonium salt (II-5) and in addition synthetic aldehyde (II-6) through Wittig reaction condensation, behind the alkene body that then reduction obtains, through to blocking group R bDeprotection obtains the reaction of phenol property midbody (II-7).As the condition of Wittig reaction, can enumerate the condition of using in the common Wittig reaction.For example in ether series solvents such as THF, use alkali such as tert.-butoxy potassium, carry out about 30 minutes～12 hours at-30 ℃～reflux temperature.Make with extra care through silica gel column chromatography, recrystallize etc. through usual method stopped reaction, extraction, cleaning, drying, removal solvent etc. as required the reaction back, obtains title product.The reagent that uses in the reduction as the two keys that then carry out; So long as the reagent that uses in the common olefin reduction; Not restriction can be enumerated and for example use the contact hydrogenation that carries the palladium gac or draw heterogeneous catalyst such as nickel how or rhodium coordination compound homogeneous catalysts such as (chloro three (triphenylphosphine) rhodiums (I) etc.).As reaction conditions, can enumerate in hydrocarbon solvents such as ether series solvent such as pure series solvent 、 dioxs such as ethanol or toluene, under 1～20 atmospheric hydrogen-pressure, ice-cold down～reflux and carry out 30 minutes～1 time-of-week.In addition, according to stability of speed of response or compound etc., also can in reaction solution, add alkali such as acid such as acetic acid or triethylamine.Pass through usual method filtration, extraction, cleaning, drying, removal solvent etc. after reacting, make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.As the blocking group R that carries out continuously bThe condition of deprotection is so long as at R bDeprotection in use, not special restriction is for example at R bWhen being methyl; In dichloromethane solvent, use lewis acidic methods such as boron tribromide; When being acyl groups such as ethanoyl; In the mixed solvent of pure series solvent and water, use mineral alkalis such as sodium hydroxide method, be ethers such as methoxymethyl, THP trtrahydropyranyl, the tertiary butyl when being blocking group, use the method for acid such as hydrochloric acid or trifluoracetic acid etc.In addition, use at R bWhen last benzyl or substituted benzyl, benzyloxymethyl etc. add the blocking group of Hydrogen Energy deprotection through contact, R bDeprotection can carry out simultaneously with the reduction of the above-mentioned pair of key.And, at R bIn when using heptyl, do not need R bDeprotection, below in the step alkylation of phenol also can omit.
The 6th step is the phenolic hydroxyl group of alkylation midbody (II-7), then passes through at R c, R dAnd R 2When having hydroxyl respectively to blocking group R e(R eWith above-mentioned equivalent in meaning) deprotection, obtain the reaction of The compounds of this invention (I-1).The reagent that uses in the alkylation of the phenolic hydroxyl group that midbody (II-7) has can be enumerated the combination of alkylating agents such as halo heptyl and mineral alkalis such as salt of wormwood or sodium hydride.As reaction conditions, can enumerate at N, in the ether series solvents such as dinethylformamide isopolarity solvent or THF, under ice-cold～80 ℃, carry out about 30 minutes～12 hours.And, have in the alkylation of phenolic hydroxyl group of midbody (II-7), use azodicarboxy acid derivatives such as phosphine compound such as triphenylphosphine and azo-2-carboxylic acid's diisopropyl ester, condensation heptyl alcoholic acid light prolongs reaction (Mitsunobu Reaction) also can be used.As the reaction conditions of this moment, can enumerate in ether series solvents such as THF, ice-coldly carry out about 10 minutes～6 hours under～50 ℃ down.After the reaction,, make with extra care through silica gel column chromatography, recrystallize etc. as required, can obtain title product through usual method extraction, cleaning, drying, removal solvent etc.In the deprotection that then carries out, so long as usually use in the deprotection of blocking group, not special restriction, can be whole blocking groups once or the substep deprotection.For example at R cAnd R eIn conjunction with forming cyclic acetal, R dWhen being tert-butoxycarbonyl, can the while deprotection through acid.The acid of this moment can have been enumerated mineral acid such as hydrochloric acid or trifluoracetic acid etc.And as reaction conditions, can enumerate in ether series solvent, water or their mixed solvents such as ethanol property solvent such as ethanol or THF, ice-coldly carry out about 10 minutes～12 hours under～80 ℃ down.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, obtain title product.
2) in the The compounds of this invention, R is that Wasserstoffatoms, X are Sauerstoffatom, R in the general formula (Ia) 1Be that the compound (I-1) shown in 1～4 the alkyl is to use midbody (II-2, the R that contains in the circuit (II) for the substituted carbonatoms of halogen atom aWhen being H) or come synthetic according to following circuit (III) synthetic midbody (III-1) from the known compound shown in the general formula (III-2).
[chemical formula 5]
Circuit (III)
(in the formula, R bBe blocking group, R f-OH is the ethanol that in the solubilizing agent decomposition reaction, uses, R 1The substituted carbonatoms of expression halogen atom is 1～4 alkyl.)
R in the formula bAnd circuit (II) is equivalent in meaning.And, as R fMethyl, ethyl, benzyl etc. can have been enumerated.In the above-mentioned circuit, synthetic about from compound (II-2) used the general reaction conditions of Arndt-Eistert reaction.And, in the reduction of thus obtained ester, can enumerate reagent and the condition in second step of circuit (II), used.And, in the above-mentioned circuit, synthetic about from compound (III-2), the condition of using common Wittig to react.In the s.t., in the mixed solvent of organic solvent such as water or THF and water, use mineral acids such as hydrochloric acid thereafter.In reduction thereafter, use lithium aluminum hydride or Peng Qinghuana etc. the metallic hydrogen coordination compound, carry the palladium gac or draw nickel how etc. heterogeneous catalyst or rhodium coordination compound homogeneous catalysts such as (chloro three (triphenylphosphine) rhodiums (I) etc.) the contact hydrogenation or it is carried out successively continuously.The midbody of the ethanol property that obtains in this circuit (III-1) is can be transformed into The compounds of this invention through known method (for example journal of medicinalchemistry (ジ ヤ one Na Le オ Block メ デ イ シ Na Le ケ ミ ス ト リ one) the 43rd volume (2000) 2946-2961 page or leaf).
3) (R of I in a) is that Wasserstoffatoms, X are Sauerstoffatom, R to general formula 1The compound (I-2) that is trifluoromethyl or cyanic acid is through with line (IV) synthetic.
[chemical formula 6]
Circuit (IV)
Figure S2006800472557D00111
(in the formula, R c, R dThe expression blocking group, X a, X cThe expression leavings group, R 1Expression trifluoromethyl or cyanic acid, R 2With above-mentioned equivalent in meaning.)
R in the formula c, R d, X aWith above-mentioned equivalent in meaning.As X c represents a leaving group as long as the Sonogashira (Yuan head) the reaction can be activated through the catalyst leaving group is not particularly limited.Halogen atom (preferred iodine atom, bromine atoms etc.), trifluoromethane sulfonyloxy etc. for example can have been enumerated.
First step is through having leaving group X aCompound (IV-1) and heptyl ethanol condensed, obtain the reaction of midbody (IV-2).This step can be at N, in the ether series solvents such as polar solvent of dinethylformamide or DMSO 99.8MIN. and so on or THF, in the presence of alkali, carry out.Can use mineral alkalis, 1 such as sodium hydride or Pottasium Hydroxide as alkali, 8-diazonium two ring [5.4.0] 11 carbon-organic basess such as 7-alkene carry out.As reaction conditions, can enumerate about ice-cold～100 ℃ and carry out about 10 minutes～10 hours.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care through distillation, silica gel column chromatography, recrystallize etc. as required, can obtain title product.
Second step is that midbody (IV-2) and midbody (II-6) pass through known method (for example tetrahedron the 57th volume (calendar year 2001) 6531-6538 page or leaf, Chem.Pharm.Bull. the 53rd volume (2005) 100-102 page or leaf) synthetic midbody (IV-3); By Sonogashira reaction condensation, obtain to contain the reaction of triple-linked midbody (IV-4) again.Tetrakis triphenylphosphine palladium (0), three (dibenzalacetones), two palladiums (0), two (acetonitrile) palladium palladium compounds such as (II) of dichloro can have been enumerated as the catalyzer that uses.And, can also add copper compound, 2-dicyclohexyl phosphino-s-2 ' such as mineral alkali, cupric iodide or cupric bromide such as organic bases such as triethylamine or ammonia, additives such as phosphine compound such as 4 ', 6 '-tri isopropyl biphenyl base in order to promote reaction.Can enumerate in ether series solvent, acetonitrile or hydrocarbon solvents such as N isopolarity solvent or benzene such as THF Huo diox as reaction conditions, carry out about 30 minutes～24 hours to reflux temperature ice-cold.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
Third step is the triple bond of reduction midbody (IV-4), obtains the reaction of midbody (IV-5).The reagent that uses is so long as the reagent of the common reduction that is used for unsaturated carbon bond; Not restriction is for example enumerated to use and is carried the palladium gac or draw nickel how, carry the contact hydrogenation of heterogeneous catalyst such as palladium gac quadrol complex body, rhodium coordination compound homogeneous catalysts such as (chloro three (triphenylphosphine) rhodiums (I) etc.).As reaction conditions, can enumerate in hydrocarbon solvents such as ether series solvent such as pure series solvent 、 dioxs such as ethanol or toluene, under 1～20 atmospheric hydrogen-pressure, ice-cold down～carry out 30 minutes～1 time-of-week under refluxing.In addition, according to stability of speed of response or compound etc., also can in reaction solution, add alkali such as acid such as acetic acid or triethylamine.After the reaction, according to usual method filter, extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
The 4th step is through with midbody (IV-5) deprotection, obtains the reaction of The compounds of this invention (I-2).At R c, R dAnd R 2When having hydroxyl, at blocking group R to its protection e(R eWith aforementioned equivalent in meaning) deprotection in, so long as usually use in the deprotection of blocking group, not special restriction, all blocking groups can be once or the substep deprotection.R for example cAnd R eIn conjunction with, the acetal of formation ring-type, R dWhen being tertbutyloxycarbonyl, the acid by catalytic amount is then used more strong acidic condition to the acetal deprotection of ring-type, can carry out R dDeprotection.As the condition in the deprotection of acetal this moment; Can enumerate in the mixing solutions of ethanol property solvent such as methyl alcohol or ethanol property solvent and other organic solvents; Use the hydrochloric acid or the toluenesulphonic acids of catalytic amount, under ice-cold～80 ℃, carry out about 30 minutes～12 hours.On the other hand, the R that carries out as the deprotection of following acetal dThe deprotection condition, enumerate mineral acids such as using the above hydrochloric acid of equivalent or trifluoracetic acid etc., in ether series solvent, water or their mixed solvents such as ethanol property solvent such as ethanol or THF, under ice-cold～80 ℃, carry out about 10 minutes～12 hours.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
4) R in the general formula (Ia) is that Wasserstoffatoms, X are sulphur atom, R 1For the substituted carbonatoms of halogen atom is that the compound (I-3) that 1～4 alkyl is represented comes synthetic through following circuit (V).
[chemical formula 7]
Circuit (V)
Figure S2006800472557D00131
(in the formula, R a, R c, R dThe expression blocking group, X b, X dThe expression leavings group, R 1The substituted carbonatoms of expression halogen atom is 1～4 alkyl, R 2With aforementioned equivalent in meaning.)
R in the formula a, R c, R d, X bWith aforesaid equivalent in meaning.X dThe leavings group of expression is so long as through heptyl sulfonium ion (C 7H 15S -) group that can leave away of replacement(metathesis)reaction, not special restriction.For example enumerate halogen atom (concrete have fluorine atom etc.), tosyloxy etc.
First step is through on 4, having leavings group X dTRIMETHOXY BENZOIC ACID (FOR MANUFACTURING OF T.M. verivate (V-1) and the condensation of heptyl mercaptan, on 4, introduce heptyl sulphur, obtain the reaction of midbody (V-2).This step can be at N, in the ether series solvents such as polar solvent of dinethylformamide or DMSO 99.8MIN. and so on or THF, in the presence of alkali, carries out.As alkali, can use mineral alkali, triethylamines or 1 such as salt of wormwood or sodium hydroxide, 8-diazonium two ring [5.4.0] 11 carbon-organic basess such as 7-alkene carry out.As reaction conditions, have under about-30～80 ℃ and carry out about 10 minutes～10 hours.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care through distillation, silica gel column chromatography, recrystallize etc. as required, can obtain title product.
Second step is the carboxyl of reduction midbody (V-2), and acquisition has the reaction of the midbody (V-3) of hydroxyl.As the reagent that in reduction, uses; So long as it is normally used; Not special restriction can be enumerated basic metal or boron cpds such as metallic hydrogen coordination compound, diborane such as metal hydrides such as alkaline-earth metal, diisobutylaluminium hydride, lithium aluminum hydride or Peng Qinghuana such as sodium, use the contact hydrogenation of homogeneous phase or heterogeneous catalyzer etc.Reaction conditions is to select suitable temperature and time according to the original reagent of going back that uses.Concrete having enumerated in ether series solvents such as THF carried out about 10 minutes～12 hours-30 ℃～backflow, through diborane, lithium aluminum hydride, lithium borohydride reduction; In the mixed solvent of pure series solvent such as ethanol or ether series solvents such as pure series solvent and THF ice-cold～reflux and carry out about 30 minutes～24 hours, through Peng Qinghuana or hydroboration calcium reduction etc.After the reaction,, make with extra care through distillation, silica gel column chromatography, recrystallize etc. as required, can obtain title product according to usual method stopped reaction, extraction, cleaning, drying, removal solvent etc.
Third step is that the hydroxyl with midbody (V-3) is transformed into leavings group X bReaction.As reagent, so long as can alcohol hydroxyl group be transformed into X bReagent, not special restriction.X bThe reagent that uses when being halogen atom has the mineral acid, phosphorus tribromide, phosphorus pentabromide, phosphorus trichloride, phosphorus pentachloride, iodine, bromine, chlorine, halo thionyl of combination, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI of N-chlorosuccinimide, N-bromosuccinimide, tetracol phenixin or they and reaction auxiliarys such as triphenylphosphine, alkali and so on etc.As reaction conditions, have in organic solvents such as ether series solvent such as halogen series solvents such as methylene dichloride or THF, carrying out about 10 minutes～6 hours under-30 ℃～130 ℃.In addition,, mineral acid also can carry out the reaction of two coating systems of organic solvents such as the aqueous solution or toluene and water when using.X bThe reagent that uses during for sulfonyloxy can use the combination of chloro alkylsulfonyls such as methyl chloride alkylsulfonyl or chlorotoluene alkylsulfonyl and organic basess such as triethylamine or pyridine.As reaction conditions, can enumerate in the organic solvent of ether series solvents such as halogen series solvents such as methylene dichloride or THF etc., carrying out about 5 minutes～3 hours under-30 ℃～50 ℃.After the reaction,, make with extra care through distillation, silica gel column chromatography, recrystallize etc. as required, can obtain title product according to usual method stopped reaction, extraction, cleaning, drying, removal solvent etc.
The 4th step is with having leavings group X bThe reaction of midbody (V-4) and triphenylphosphine, the reaction of Huo De phosphonium salt (V-5).As reaction conditions, can enumerate in inert solvents such as ether, benzene, toluene, carry out about 30 minutes～6 hours in room temperature～backflow.After the reaction, carry out as required solvent heat up in a steamer, cool off, add insoluble solvents such as Di Iso Propyl Ether or hexane after, the solid that leaching is separated out can obtain title product.
The 5th step is to react phosphonium salt (V-5) and synthetic aldehyde (II-6) condensation in addition through Wittig, and next the alkene body of reduction acquisition obtains the reaction of midbody (V-6).As the condition of Wittig reaction, can enumerate the condition of using in the common Wittig reaction.For example, in ether series solvents such as THF, use alkali such as tert.-butoxy potassium, carry out about 30 minutes～12 hours-30 ℃～backflow.After the reaction,, make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product according to usual method stopped reaction, extraction, cleaning, drying, removal solvent etc.The reagent that uses in the reduction as the two keys that then carry out; So long as the reagent that uses in the common olefin reduction; Not restriction for example has and uses the contact hydrogenation that carries the palladium gac or draw heterogeneous catalyst such as nickel how or rhodium coordination compound homogeneous catalysts such as (chloro three (triphenylphosphine) rhodiums (I) etc.).As reaction conditions, can enumerate in hydrocarbon solvents such as ether series solvent such as pure series solvent 、 dioxs such as ethanol or toluene, under 1～20 atmospheric hydrogen-pressure, ice-cold～as to reflux and carry out 30 minutes～1 time-of-week.In addition, according to stability of speed of response or compound etc., also can in reaction solution, add alkali such as acid such as acetic acid or triethylamine.After the reaction, according to usual method filter, extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
The 6th step is the R at midbody (V-6) c, R dAnd R 2When having hydroxyl, through to protecting the blocking group R of these groups e(R eWith above-mentioned equivalent in meaning.) carry out deprotection, obtain the reaction of The compounds of this invention (I-3).In the deprotection of midbody (V-6), so long as in the deprotection of common blocking group, use, not special restriction can be with whole blocking groups once or the substep deprotection.For example at R cAnd R eIn conjunction with forming cyclic acetal, R dDuring for tertbutyloxycarbonyl, can be through acid while deprotection.The acid of this moment can have been enumerated mineral acid such as hydrochloric acid or trifluoracetic acid etc.And as reaction conditions, have in ether series solvent, water or their mixed solvents such as alcohol property solvent such as ethanol or THF, carry out about 10 minutes～12 hours under～80 ℃ down ice-cold.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
5) R in the general formula (Ia) is that Wasserstoffatoms, X are sulphur atom, R 1, carbonatoms substituted for halogen atom is that the compound (I-4) that 1～4 alkyl or cyanic acid are represented is through following circuit (VI) synthetic.
[chemical formula 8]
Circuit (VI)
(in the formula, R c, R dThe expression blocking group, X eThe activating group of expression hydroxyl, R 1The substituted carbonatoms of expression halogen atom is 1～4 alkyl or cyanic acid, R 2With above-mentioned equivalent in meaning.)
R in the formula c, R dWith above-mentioned equivalent in meaning.X eThe activating group of the hydroxyl of expression can have been enumerated alkylsulfonyls such as trifluoromethane sulfonyl group or tosyl group.
First step is on the phenolic hydroxyl group of the midbody of circuit (II) (II-7), to introduce the sensitization group, obtains the reaction of midbody (VI-1).This step is in ether series solvents such as halogen series solvent of methylene dichloride or chloroform and so on or THF, in the presence of alkali, carries out.The reagent that uses in this reaction has the activatory sulfonic acid of Trifluoromethanesulfonic anhydride or 1-(trifluoromethane sulfonyl group) imidazoles, chlorotoluene alkylsulfonyl and so on.And,, also can carry out this reaction through sulfonic acid and condensing agent are merged use.As alkali, can use triethylamine or organic basess such as pyridine, lutidine.Have under about-50～50 ℃ as reaction conditions and to carry out about 5 minutes～3 hours.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
Second step is through the condensation of midbody (VI-1) and heptyl mercaptan, obtains the reaction of midbody (VI-2).This step can the Zai diox etc. in the hydrocarbon solvent such as ether series solvent or toluene, in the presence of palladium catalyst, carries out.As palladium catalyst, palladium (II), three (dibenzalacetones), two palladiums (0) etc. can have been enumerated.And the reaction auxiliary as in this reaction can add phosphine compound or alkali.Phosphine compound has triphenylphosphine or 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl-oxa-anthracene etc.Mineral alkali or N such as cesium carbonate are arranged on the other hand, organic basess such as N-diisopropylethylamine as alkali.As reaction conditions, can enumerate in room temperature～backflow and carry out 30 minutes～2
About 4 hours.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
Third step is the R of midbody (VI-2) c, R dAnd R 2When having hydroxyl, through to protecting the blocking group R of these groups e(R eWith aforementioned equivalent in meaning.) carry out deprotection, obtain the reaction of The compounds of this invention (I-4).In the deprotection of midbody (VI-2), so long as in the deprotection of common blocking group, use, not special restriction can be with whole blocking groups once or the substep deprotection.R for example cBe blocking group, the R that acid can deprotection that pass through of methoxymethyl etc. dBe that tert-butoxycarbonyl is, can be through acid while deprotection.The acid of this moment has mineral acid such as hydrochloric acid or trifluoracetic acid etc.And reaction conditions has in ether series solvent, water or their mixed solvents such as ethanol property solvent such as ethanol or THF, carries out about 10 minutes～12 hours under～80 ℃ down ice-cold.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
6) in the The compounds of this invention, the R in the general formula (Ia) is P (=O) (OH) 2The compound (I-5) of expression is through following circuit (VII) synthetic.
[chemical formula 9]
Circuit (VII)
Figure S2006800472557D00171
(in the formula, X representes Sauerstoffatom or sulphur atom, R d, R gThe expression blocking group, R 1Substituted, the carbonatoms of expression halogen atom is 1～4 alkyl or cyanic acid, R 2With aforementioned equivalent in meaning.)
R in the formula dWith aforesaid equivalent in meaning.R in the formula gThe blocking group of expression is so long as can protect phosphate group, not special restriction.Alkyl (preferred carbonatoms is about 1～6 alkyl, concrete have the tertiary butyl etc.), benzyl, phenyl etc. are for example arranged.
First step is to be the amino of the compound (VII-1) of Wasserstoffatoms through the R of protection in the The compounds of this invention, the step of synthesizing amino protective (VII-2).This step can be used common amido protecting to react to carry out.Concrete, as blocking group (R d) when using acyl group, alkoxy carbonyl or carbobenzoxy-(Cbz) etc., this step can be carried out in alcohol such as methyl alcohol or in two coating systems of organic solvents such as water and vinyl acetic monomer or chloroform or the mixed solution.As the reagent that uses, acid anhydrides such as sour muriate such as chloro ethanoyl or chloro carbobenzoxy, acetic anhydride or tert-Butyl dicarbonate can have been enumerated.As the reaction promotor in this reaction, can add mineral alkalis such as organic basess such as triethylamine or sodium hydrogencarbonate.As reaction conditions, have under ice-cold～50 ℃ and carry out about 30 minutes～24 hours.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
Second step is with amido protecting body (VII-2) and phosphorylation agent (for example phosphoric acid muriate, phosphoramidite and oxygenant, tetra-sodium tetrabenzyl ester etc.) reaction, the step of synthetic phosphorylation body (VII-3).When using tetra-sodium tetrabenzyl ester as phosphorylation agent, this step can be under non-water condition, in preferred toluene, methylene dichloride, their organic solvents such as mixed solvent, uses additive (for example silver suboxide, iodate four just own ammonium etc.) to carry out.As reaction conditions, have under ice-cold～50 ℃ and carry out about 5～24 hours.After the reaction, according to usual method filter, extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.And this reaction is based on known method and comes common phosphorylation agent (phosphoric acid muriate and alkali, phosphoramidite and oxygenant etc.) reaction synthetic.
Third step is the step from phosphoric acid oxysome (VII-3) preparation The compounds of this invention (I-5).This step can use common deprotection reaction to carry out.The concrete hydrogenation that can carry out decomposes, uses Lewis acids such as acid, bromination trimethyl silyl such as hydrochloric acid or trifluoracetic acid to carry out.When using hydrogenation to decompose in this reaction, having enumerated this step is in alcohol property solvents such as methyl alcohol, uses catalyzer such as carrying the palladium gac, under atmosphere of hydrogen gas, carries out.As reaction conditions, have under room temperature～60 ℃ and carry out about 1～24 hour.Reaction solution is to filter, concentrate etc. according to usual method, is made with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.And the reaction conditions when using acid in this reaction can be enumerated in the mixed solvent of alcohol property solvent such as ethanol or they and water, ℃ carries out about 30 minutes～12 hours from room temperature～100.
7) in the The compounds of this invention, the R in the general formula (I) is that Wasserstoffatoms, X are that Sauerstoffatom, Y are CH 2CH 2, R 1, carbonatoms substituted for halogen atom is 1～4 alkyl or cyanic acid, R 3And R 4The compound of representing for Wasserstoffatoms (I-1a) is to come synthetic through following circuit (VIII).
[Chemical formula 1 0]
Route (VIII)
(in the formula, n is 5～8, R aBe Wasserstoffatoms or blocking group, R b, R c, R dBe blocking group, X a, X bBe leavings group, R 1Be that halogen atom is substituted, carbonatoms is 1～4 alkyl or cyanic acid, R 2With aforementioned equivalent in meaning.)
R in the formula aSo long as the group of protection Wasserstoffatoms or carboxyl, not special restriction.Alkyl (concrete have methyl, ethyl etc.), aralkyl (benzyl etc.) and and R are for example arranged bIdentical substituting group etc.R in the formula bSo long as the group of protection phenolic hydroxyl group, not special restriction.Alkyl (concrete is methyl, ethyl etc.), aralkyl (benzyl etc.) etc. are for example arranged.As R bUse the part-structure of invention compound (I-1a) to be-(CH 2) nCH 3When (n and aforementioned equivalent in meaning), need not be with R bDeprotection also can obtain inventing compound (I-1a).R in the formula cSo long as the group of protection hydroxyl, not special restriction.The substituting group (methoxymethyl, THP trtrahydropyranyl etc. are specifically arranged) that acyl group (preferred carbonatoms is about 2～4 group, and ethanoyl etc. is specifically arranged), trialkylsilkl (trimethyl silyl etc. is specifically arranged), benzyl or formation acetal compound are for example arranged.R 2When having hydroxyl, this blocking group R e(as R eConcrete and R cThe same) and R cIn conjunction with, can form the cyclic acetal.R in the formula dShown blocking group is so long as the amino group of protection, not restriction especially.Acyl group (preferred carbonatoms is about 2～4 group, and ethanoyl etc. is specifically arranged), carbamate (tertbutyloxycarbonyl or carbobenzoxy-(Cbz) etc. are specifically arranged) etc. are for example arranged.And X aShown leavings group is so long as through pure ion (R b-O -) replacement(metathesis)reaction the time group that breaks away from, not special restriction.Halogen atom (fluorine atom etc. is specifically arranged), tosyloxy etc. are for example arranged.X bShown leavings group is so long as slough when midbody (VIII-4) and triphenylphosphine condensation, do not hinder reaction, not special restriction during below Wittig reaction.Halogen atom (being specially iodine atom, bromine atoms, chlorine atom etc.), methanesulfonyloxy group, tosyloxy etc. are for example arranged.
First step is through on 4, having leavings group X aTRIMETHOXY BENZOIC ACID (FOR MANUFACTURING OF T.M. verivate (II-1) and the condensation of alcohol (VIII-1), on 4, introduce and have blocking group R bOxygen functional group, obtain the reaction of midbody (VIII-2).This step is at N, in the ether series solvents such as dinethylformamide or DMSO 99.8MIN. isopolarity solvent or THF, in the presence of alkali, carries out.As alkali, can use mineral alkalis, 1 such as sodium hydride or Pottasium Hydroxide, 8-diazonium two ring [5.4.0] 11 carbon-organic basess such as 7-alkene carry out.Reaction conditions can have been enumerated at ice-cold following about～100 ℃ and carry out about 10 minutes～10 hours.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care through distillation, silica gel column chromatography, recrystallize etc. as required, can obtain title product.
Second step is the carboxyl of reduction midbody (VIII-2), and acquisition has the reaction of the midbody (VIII-3) of hydroxyl.As the reagent that uses in the reduction; So long as it is normally used; Not special restriction can be enumerated basic metal or boron cpds such as metallic hydrogen coordination compound, diborane such as metal hydrides such as alkaline-earth metal, diisobutylaluminium hydride, lithium aluminum hydride or Peng Qinghuana such as sodium, use the contact hydrogenation of homogeneous phase or heterogeneous catalyst etc.Reaction conditions is selected suitable temperature and time according to the original reagent of going back that uses.Concrete can enumerate in ether series solvents such as THF ,-30 ℃～refluxed about 10 minutes～12 hours, through diborane, lithium aluminum hydride, lithium borohydride reduction; In the mixed solvent of pure series solvents such as ethanol or ether series solvents such as pure series solvent and THF, carry out about 30 minutes～24 hours at ice-cold～reflux temperature, with Peng Qinghuana or hydroboration calcium reduction etc.After the reaction,, make with extra care through distillation, silica gel column chromatography, recrystallize etc. as required, can obtain title product according to usual method stopped reaction, extraction, cleaning, drying, removal solvent etc.
Third step is that the hydroxyl with midbody (VIII-3) is transformed into leavings group X bReaction.As reagent, so long as can alcoholic extract hydroxyl group be transformed into X bReagent, not special restriction.X bThe reagent that uses when being halogen atom can be enumerated the mineral acid, phosphorus tribromide, phosphorus pentabromide, phosphorus trichloride, phosphorus pentachloride, iodine, bromine, chlorine, halo thionyl of combination, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI of N-chlorosuccinimide, N-bromosuccinimide, tetracol phenixin or they and reaction auxiliarys such as triphenylphosphine, alkali and so on etc.Reaction conditions has in organic solvents such as ether series solvent such as halogen series solvent of methylene dichloride etc. or THF, is carrying out about 10 minutes～6 hours under-30 ℃～130 ℃.In addition,, mineral acid under two coating systems of organic solvents such as the aqueous solution or toluene and water, reacts when using.X bThe reagent that uses during for sulfonyloxy has the combination of chloro alkylsulfonyls such as methyl chloride alkylsulfonyl or chlorotoluene alkylsulfonyl and organic basess such as triethylamine or pyridine.As reaction conditions, can enumerate in organic solvents such as ether series solvent such as halogen series solvents such as methylene dichloride or THF, carrying out about 5 minutes～3 hours under-30 ℃～50 ℃.After the reaction,, make with extra care through distillation, silica gel column chromatography, recrystallize etc. as required, can obtain title product according to usual method stopped reaction, extraction, cleaning, drying, removal solvent etc.
The 4th step is with having leavings group X bThe reaction of midbody (VIII-4) and triphenylphosphine, the reaction of Huo De phosphonium salt (VIII-5).As reaction conditions, can enumerate in inert solvents such as diethyl ether, benzene, toluene, carry out about 30 minutes～12 hours at room temperature～reflux temperature.After the reaction, carry out as required solvent heat up in a steamer, cool off, add insoluble solvents such as Di Iso Propyl Ether or hexane after, the solid that leaching is separated out can obtain title product.
The 5th step is through the anti-Suo of the answering He of Wittig phosphonium salt (VIII-5) and other synthetic aldehyde (II-6), behind the alkene body that next reduction obtains, through to blocking group R bDeprotection obtains the reaction of phenol property midbody (VIII-6).As the condition of Wittig reaction, can enumerate the condition of using in the common Wittig reaction.For example have in ether series solvents such as THF, use alkali such as potassium tert.-butoxy thing, carry out about 30 minutes～12 hours at-30 ℃～reflux temperature.After the reaction,, make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product according to usual method stopped reaction, extraction, cleaning, drying, removal solvent etc.The reagent that uses in the reduction as the following two keys that carry out; So long as the reagent that uses in the common olefin reduction; Not restriction can be enumerated and use the contact hydrogenation that carries the palladium gac or draw heterogeneous catalyst such as nickel how or rhodium coordination compound homogeneous catalysts such as (chloro three (triphenylphosphine) rhodiums (I) etc.).As reaction conditions, can enumerate in hydrocarbon solvents such as ether series solvent such as pure series solvent 、 dioxs such as ethanol or toluene, under 1～20 atmospheric hydrogen-pressure, ice-cold down～reflux temperature carries out 30 minutes～1 time-of-week.In addition, according to stability of speed of response or compound etc., can in reaction solution, add alkali such as acid such as acetic acid or triethylamine.After the reaction, according to usual method filter, extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.As the blocking group R that carries out continuously bThe condition of deprotection, so long as R bDeprotection in use, not special restriction for example can not enumerated R bBe the words of methyl; In dichloromethane solvent, use lewis acidic methods such as boron tribromide; Be the words of acyl groups such as ethanoyl; In the mixed solvent of pure series solvent and water, using the method for mineral alkalis such as sodium hydroxide, is that methoxyl methyl or ethers such as THP trtrahydropyranyl, the tertiary butyl are blocking group, uses the method for acid such as hydrochloric acid or trifluoracetic acid etc.In addition, at R bOn benzyl substituted benzyl or benzyloxymethyl etc. can be through contact hydrogenation deprotection blocking group in use, R bDeprotection can carry out simultaneously with the reduction of above-mentioned pair of key.And, use as R bInvention compound (I-1a) part-structure promptly-(CH 2) nCH 3(n and aforementioned equivalent in meaning.) time, R bNeedn't deprotection, the alkylation of phenol also can be omitted in the step below.
The 6th step is the phenolic hydroxyl group alkylation with midbody (VIII-6), next at R c, R dAnd R 2When having hydroxyl, through protecting the blocking group R of these groups e(R eWith aforementioned equivalent in meaning.) deprotection, obtain the reaction of The compounds of this invention (I-1a).The reagent that uses in the alkylation process as the phenolic hydroxyl group with midbody (VIII-6) can be enumerated the combination of alkylating agents such as halo heptyl and mineral alkalis such as salt of wormwood or sodium hydride.As reaction conditions, can enumerate at N, in the ether series solvents such as dinethylformamide isopolarity solvent or THF, under ice-cold following～80 ℃, carry out about 30 minutes～12 hours.And, in the alkylation process of the phenolic hydroxyl group that midbody (VIII-6) has, can use azo-carboxylic acid's verivates such as phosphine compound such as triphenylphosphine and azo-2-carboxylic acid's diisopropyl ester, it is also passable to use the light of condensation heptyl ethanol etc. to prolong reaction.As the reaction conditions of this moment, enumerated in ether series solvents such as THF, under ice-cold following～50 ℃, carried out about 10 minutes～6 hours.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.Next in the deprotection that carries out, so long as usually use in the deprotection of blocking group, not special restriction, all blocking groups can be once or the substep deprotection.R for example cAnd R eIn conjunction with forming cyclic acetal, R dWhen being tertbutyloxycarbonyl, can be through acid while deprotection.The acid of this moment has mineral acid such as hydrochloric acid or trifluoracetic acid etc.And as reaction conditions, have in ether series solvent, water or their mixed solvents such as alcohol property solvent such as ethanol or THF, carry out about 10 minutes～12 hours under～80 ℃ down ice-cold.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
8) in the The compounds of this invention, the R in the general formula (I) is that Wasserstoffatoms, X are that Sauerstoffatom, Y are CH 2CH 2, R 1, carbonatoms substituted for halogen atom is 1～4 alkyl or cyanic acid, R 3And R 4The compound of representing for Wasserstoffatoms (I-1a) is from by the midbody that contains (VIII) (VIII-2, R aDuring for H) or the compound of general formula (IX-2) expression according to following circuit (IX) synthetic midbody (IX-1), use this midbody to synthesize.
[Chemical formula 1 1]
Circuit (IX)
Figure S2006800472557D00221
(in the formula, R 1Be that the substituted carbonatoms of halogen atom is 1～4 alkyl, R bBe blocking group, R f-OH is the alcohol that uses in the solubilizing agent decomposition reaction.)
R in the formula bAnd equivalent in meaning in the circuit (VIII).And, as R fMethyl, ethyl, benzyl etc. can have been enumerated.In the above-mentioned circuit, synthetic about from compound (VIII-2) used the general reaction conditions of Arndt-Eistert reaction.And, in the reduction of thus obtained ester group, can enumerate reagent and the condition in second step of circuit (VIII), used.And in the above-mentioned circuit, synthetic about from compound (IX-2), the condition of using common Wittig to react.In the s.t., in the mixed solvent of organic solvent such as water or THF and water, use mineral acids such as hydrochloric acid thereafter.In reduction thereafter, use metallic hydrogen coordination compoundes such as lithium aluminum hydride or Peng Qinghuana, carry the palladium gac or draw heterogeneous catalyst such as nickel how or rhodium coordination compound (chloro three (triphenylphosphine) rhodium (I) etc.) homogeneous catalyst of etc.ing the contact hydrogenation, perhaps carry out continuously successively.The midbody of the ethanol property that obtains in this circuit (IX-1) is incorporated in the The compounds of this invention through known method (for example journal of medicinal chemistry the 43rd volume (2000) 2946-2961 page or leaf).
9) in the The compounds of this invention, the R in the general formula (I) is Wasserstoffatoms, R 1, carbonatoms substituted for halogen atom is 1～4 alkyl or cyanic acid, R 2Be ω-fluoro-alkyl, R 3And R 4For the represented compound of Wasserstoffatoms (I-1c) is through following circuit synthetic.
[Chemical formula 1 2]
Circuit X
Figure S2006800472557D00231
(in the formula, m is 1～4 integer, and X is that Sauerstoffatom or sulphur atom, Y are CH 2CH 2Or CH=C
H, R 1, carbonatoms substituted for halogen atom is 1～4 alkyl or cyanic acid, n and aforementioned equivalent in meaning.)
First step is to be Wasserstoffatoms, R through the R in protection general formula (I) 2Be the compound (I-1b) of ω-hydroxyalkyl, the step of He oxazoline body (X-1).This step is at acetonitrile or N, in the hydrocarbon solvents such as halogen series solvent such as dinethylformamide isopolarity solvent, methylene dichloride or toluene, uses ortho-acetate to react as reagent.And in order to promote reaction, can add N, acid such as alkali such as N-diisopropylethylamine or tosic acid.As reaction conditions, can enumerate at room temperature～reflux temperature carries out about 30 minutes～12 hours.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
Second step is the hydroxyl through fluorinated compound (X-1), the step of synthetic fluorochemical (X-2).Can enumerate three as fluorizating agent and fluoridize diethylamino sulphur (DAST) or 2,2-two fluoro-1,3-methylimidazole alkane (DFI) etc.This step can be reacted in hydrocarbon solvents such as halogen series solvents such as methylene dichloride or hexane.As reaction conditions, can enumerate and carry out under-78 ℃～room temperature about 30 minutes～12 hours.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.And, after this step can be transformed into the hydroxyl of compound (X-1) corresponding sulphonate, carry out through the method for effect fluoride ion.When for example using p-toluenesulfonyl fluorochemical or TBuA fluorochemical (TBAF), in ether series solvents such as THF, ℃ following reaction is about 1 hour～24 hours in room temperature～80.Can add dewatering agents such as molecular sieve in this reaction.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
Third step is through to compound (X-2) deprotection, prepares the step of The compounds of this invention (I-1c).This step is to use common deprotection reaction to carry out.The concrete acid such as hydrochloric acid or trifluoracetic acid of using are carried out.As reaction conditions, can enumerate in the mixed solvent of alcohol property solvent such as ethanol or they and water, under room temperature～100 ℃, carry out about 30 minutes～12 hours.Reaction solution is to filter, concentrate etc. according to usual method, is made with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
10) R in the general formula (I) is that Wasserstoffatoms, X are that Sauerstoffatom, Y are CH 2CH 2, R 1Be trifluoromethyl or cyanic acid, R 3And R 4The compound of representing for Wasserstoffatoms (I-2a) is to come synthetic through following circuit (XI).
[Chemical formula 1 3]
Circuit XI
Figure S2006800472557D00241
(in the formula, R 1Expression trifluoromethyl or cyanic acid, R c, R dThe expression blocking group, X a, X cThe expression leavings group, R 2, n and aforementioned equivalent in meaning.)
R in the formula c, R d, X aWith aforesaid equivalent in meaning.As X cThe leavings group of expression, so long as the group that when Sonogashira reacts, also breaks away from through the sensitization of catalyzer ability, not special the restriction.Halogen atom (preferred iodine atom, bromine atoms etc.), trifluoromethane sulfonyloxy etc. are for example arranged.
First step is the X that has leaving group through condensation aCompound (XI-1) and alcohol (XI-2), obtain the reaction of midbody (XI-3).This step is at N, in the ether series solvents such as polar solvent of dinethylformamide or methyl-sulphoxide and so on or THF, in the presence of alkali, carries out.As alkali, can use mineral alkalis such as sodium hydride or Pottasium Hydroxide, 1,8-diazonium two ring [5.4.0] 11 carbon-organic basess such as 7-alkene carry out.As reaction conditions, can enumerate under ice-cold following about～100 ℃ and carry out about 10 minutes～10 hours.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care through distillation, silica gel column chromatography, recrystallize etc. as required, can obtain title product.
Second step is through Sonogashira reaction condensation midbody (XI-3) and midbody (IV-3), obtains to contain the reaction of triple-linked midbody (XI-4).As the catalyzer that uses, can enumerate the palladium compound of tetrakis triphenylphosphine palladium (0), three (dibenzalacetones), two palladiums (0), two (acetonitrile) palladiums (II) of dichloro etc.And, can also add copper compound, 2-dicyclohexyl phosphino-s-2 ' such as mineral alkali, cupric iodide or cupric bromide such as organic bases such as triethylamine or ammonia, additives such as phosphine compound such as 4 ', 6 '-tri isopropyl biphenyl base in order to promote reaction.As reaction conditions, can enumerate in ether series solvent, acetonitrile or hydrocarbon solvents such as N isopolarity solvent or benzene such as THF Huo diox, carry out about 30 minutes～24 hours at ice-cold time～reflux temperature.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
Third step is the triple bond of reduction midbody (XI-4), obtains the reaction of midbody (XI-5).As the reagent that uses; So long as the reagent that uses in the reduction of common unsaturated carbon bond; Not restriction is for example enumerated to use and is carried the palladium gac or draw nickel how, carry the contact hydrogenation of heterogeneous catalyst such as palladium gac quadrol complex body, rhodium coordination compound homogeneous catalysts such as (chloro three (triphenylphosphine) rhodiums (I) etc.).As reaction conditions, can enumerate in hydrocarbon solvents such as ether series solvent such as pure series solvent 、 dioxs such as ethanol or toluene, under 1～20 atmospheric hydrogen-pressure, ice-cold down～reflux temperature carries out 30 minutes～1 time-of-week.In addition, according to stability of speed of response or compound etc., also can in reaction solution, add alkali such as acid such as acetic acid or triethylamine.After the reaction, according to usual method filter, extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
The 4th step is through to midbody (XI-5) deprotection, obtains the reaction of The compounds of this invention (I-2a).R c, R dAnd R 2When having hydroxyl, at the blocking group R of these groups of protection e(R eWith aforementioned equivalent in meaning.) the deprotection process in, so long as in the deprotection of common blocking group, use, not special restriction, all blocking groups can be once or the substep deprotection.R for example cAnd R eIn conjunction with forming cyclic acetal, R dDuring for tertbutyloxycarbonyl, the acid through catalytic amount is then used stronger acidic conditions to cyclic acetal deprotection, carries out R dDeprotection.The condition of using in the deprotection as acetal this moment; Can enumerate in the mixing solutions of alcohol property solvent such as methyl alcohol or alcohol property solvent and other organic solvents; Use the hydrochloric acid or the toluenesulphonic acids of catalytic amount, under ice-cold following～80 ℃, carry out about 30 minutes～12 hours.On the other hand, the then deprotection of acetal and the R that carries out dThe condition of deprotection mineral acids such as using the above hydrochloric acid of equivalent or trifluoracetic acid etc. are arranged, in ether series solvent, water or their mixed solvents such as alcohol property solvent such as ethanol or THF, carry out 10 minutes～1 under～80 ℃ down ice-cold
About 2 hours.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
11) R in the general formula (I) is that Wasserstoffatoms, X are that sulphur atom, Y are CH 2CH 2, R 1, carbonatoms substituted for halogen atom is 1～4 alkyl, R 3And R 4The compound of representing for Wasserstoffatoms (I-3a) is to come synthetic through following circuit (X I I).
[Chemical formula 1 4]
Circuit (XII)
Figure S2006800472557D00261
(in the formula, R 1, carbonatoms substituted for halogen atom is 1～4 alkyl, R aBe Wasserstoffatoms or blocking group, R c, R dBe blocking group, X b, X dBe leavings group, R 2, n and aforementioned equivalent in meaning.)
R in the formula a, R c, R d, X bAnd X dWith aforesaid equivalent in meaning.X dThe leavings group of expression is so long as through alkyl sulfide ion (CH 3(CH 2) nS -) replacement(metathesis)reaction the time group that can break away from, not special restriction.Halogen atom (concrete have fluorine atom etc.), tosyloxy etc. are for example arranged.
First step is to have leavings group X through in 4 of the condensations dTRIMETHOXY BENZOIC ACID (FOR MANUFACTURING OF T.M. verivate (V-1) and mercaptan (XII-1), on 4, introduce alkyl sulfide, obtain the reaction of midbody (XII-2).This step is at N, in the ether series solvents such as polar solvent of dinethylformamide or DMSO 99.8MIN. and so on or THF, in the presence of alkali, carries out.As alkali, can use mineral alkali, triethylamines or 1 such as salt of wormwood or sodium hydroxide, 8-diazonium two ring [5.4.0] 11 carbon-organic basess such as 7-alkene carry out.As reaction conditions, can enumerate under about-30～80 ℃ and carry out about 10 minutes～10 hours.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care through distillation, silica gel column chromatography, recrystallize etc. as required, can obtain title product.
Second step is the carboxyl of reduction midbody (XII-2), and acquisition has the reaction of the midbody (XII-3) of hydroxyl.As the reagent that in reduction, uses; So long as it is normally used; Not special restriction can be enumerated basic metal or boron cpds such as metallic hydrogen coordination compound, diborane such as metal hydrides such as alkaline-earth metal, diisobutylaluminium hydride, lithium aluminum hydride or Peng Qinghuana such as sodium, use the contact hydrogenation of homogeneous phase or heterogeneous catalyst etc.Reaction conditions is gone back original reagent and can be selected suitable temperature and time according to what use.Concrete, have in ether series solvents such as THF, under-30 ℃～reflux temperature carries out about 10 minutes～12 hours, reduces with diborane, lithium aluminum hydride, lithium borohydride; In the mixed solvent of pure series solvent such as ethanol or ether series solvents such as pure series solvent and THF, ice-cold down～reflux temperature carries out about 30 minutes～24 hours, with Peng Qinghuana or hydroboration calcium reduction etc.After the reaction,, make with extra care through distillation, silica gel column chromatography, recrystallize etc. as required, can obtain title product according to usual method stopped reaction, extraction, cleaning, drying, removal solvent etc.
Third step is that the hydroxyl with midbody (XII-3) is transformed into leavings group X bReaction.As reagent, so long as can alcohol hydroxyl group be transformed into X bReagent, not special restriction.X bThe reagent that uses during for halogen atom has the mineral acid, phosphorus tribromide, phosphorus pentabromide, phosphorus trichloride, phosphorus pentachloride, iodine, bromine, chlorine, halo thionyl of combination, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI of N-chlorosuccinimide, N-bromosuccinimide, tetracol phenixin or they and reaction auxiliarys such as triphenylphosphine, alkali and so on etc.As reaction conditions, have in organic solvents such as ether series solvent such as halogen series solvents such as methylene dichloride or THF, carrying out about 10 minutes～6 hours under-30 ℃～130 ℃.In addition,, mineral acid also can carry out the reaction of two coating systems of organic solvents such as the aqueous solution or toluene and water when using.X bThe reagent that uses during for sulfonyloxy can use the combination of chloro alkylsulfonyls such as methyl chloride alkylsulfonyl or chlorotoluene alkylsulfonyl and organic basess such as triethylamine or pyridine.As reaction conditions, can enumerate in organic solvents such as ether series solvent such as halogen series solvents such as methylene dichloride or THF, carrying out about 5 minutes～3 hours under-30 ℃～50 ℃.After the reaction,, make with extra care through distillation, silica gel column chromatography, recrystallize etc. as required, can obtain title product according to usual method stopped reaction, extraction, cleaning, drying, removal solvent etc.
The 4th step is with having leavings group X bThe reaction of midbody (XII-4) and triphenylphosphine, the reaction of Huo De phosphonium salt (XII-5).As reaction conditions, can enumerate in inert solvents such as diethyl ether, benzene, toluene, the room temperature refluxed is about 30 minutes～6 hours.After the reaction, carry out as required solvent heat up in a steamer, cool off, add insoluble solvents such as Di Iso Propyl Ether or hexane after, the solid that leaching is separated out can obtain title product.
The 5th step is that next the alkene body of reduction acquisition obtains the reaction of midbody (XII-6) through the anti-Suo of the answering He of Wittig phosphonium salt (XII-5) and other synthetic aldehyde (II-6).As the condition of Wittig reaction, can enumerate the condition that common Wittig reaction is used down.For example in ether series solvents such as THF, use alkali such as tert.-butoxy potassium, under-30 ℃～reflux temperature carries out about 30 minutes～12 hours.After the reaction,, make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product according to usual method stopped reaction, extraction, cleaning, drying, removal solvent etc.As the reagent that uses in two key reduction of next carrying out; So long as the reagent that uses in the common olefin reduction; Not restriction has and uses the contact hydrogenation that carries the palladium gac or draw heterogeneous catalyst such as nickel how or rhodium coordination compound homogeneous catalysts such as (chloro three (triphenylphosphine) rhodiums (I) etc.).As reaction conditions, can enumerate in hydrocarbon solvents such as ether series solvent such as pure series solvent 、 dioxs such as ethanol or toluene, under 1～20 atmospheric hydrogen-pressure, ice-cold down～reflux temperature carries out 30 minutes～1 time-of-week.In addition, according to stability of speed of response or compound etc., can in reaction solution, add alkali such as acid such as acetic acid or triethylamine.After the reaction, according to usual method filter, extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
The 6th step is the R at midbody (XII-6) c, R dAnd R 2When having hydroxyl to protecting the blocking group R of these hydroxyls e(R eWith aforementioned equivalent in meaning.) carry out deprotection, obtain the reaction of The compounds of this invention (I-3a).In the deprotection of midbody (XII-6), so long as usually use in the deprotection of blocking group, not special restriction can be with whole blocking groups once or the substep deprotection.R for example cAnd R eIn conjunction with forming cyclic acetal, R dDuring for tertbutyloxycarbonyl, can be through acid while deprotection.As the acid of this moment, mineral acid such as hydrochloric acid or trifluoracetic acid etc. are arranged.And as reaction conditions, have in ether series solvent, water or their mixed solvents such as ethanol property solvent such as ethanol or THF, carry out about 10 minutes～12 hours under～80 ℃ down ice-cold.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
12) R in the general formula (I) is that Wasserstoffatoms, X are sulphur atom, R 1, carbonatoms substituted for halogen atom is 1～4 alkyl or cyanic acid, R 3And R 4The compound of representing for Wasserstoffatoms (I-4a) is through following circuit (XIII) synthetic.
[Chemical formula 1 5]
Circuit (XIII)
Figure S2006800472557D00281
(in the formula, R 1, carbonatoms substituted for halogen atom is 1～4 alkyl or cyanic acid, R c, R dBe blocking group, X eBe the sensitization group of hydroxyl, Y is CH 2CH 2Or CH=CH, R 2, n and aforementioned equivalent in meaning.)
R in the formula c, R dWith aforesaid equivalent in meaning.X eThe sensitization group of the hydroxyl of expression can have been enumerated alkylsulfonyls such as trifluoromethane sulfonyl group or tosyl group.
First step is on the phenolic hydroxyl group of the midbody of circuit (VIII) (VIII-6), to introduce activating group, obtains the reaction of midbody (XIII-1).This step can be carried out in the presence of alkali in ether series solvents such as the halogen series solvent of methylene dichloride or chloroform and so on or THF.The reagent that uses in this reaction can use the activatory sulfonic acid of Trifluoromethanesulfonic anhydride or 1-(trifluoromethane sulfonyl group) imidazoles, chlorotoluene alkylsulfonyl and so on.And sulfonic acid and condensing agent are used together, also can carry out this reaction.Can use triethylamine or organic basess such as pyridine, lutidine to carry out as alkali.As reaction conditions, can enumerate under about-50～50 ℃ and carry out about 5 minutes～3 hours.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
Second step is through condensation midbody (XIII-1) and mercaptan (XII-1), obtains the reaction of midbody (XIII-2).This step is in the hydrocarbon solvents such as ether series solvents such as Zai diox or toluene, in the presence of palladium catalyst, carries out.As palladium catalyst, palladium (II), three (dibenzalacetones), two palladiums (0) etc. can have been enumerated.And the reaction auxiliary as in this reaction can add phosphine compound or alkali.Triphenylphosphine or 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl-oxa-anthracene etc. can have been enumerated as phosphine compound.On the other hand, mineral alkali or N such as cesium carbonate can have been enumerated as alkali, organic basess such as N-diisopropylethylamine.As reaction conditions, can enumerate at room temperature～reflux temperature carries out about 30 minutes～24 hours.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
Third step is the R at midbody (XIII-2) c, R dAnd R 2When having hydroxyl, to protecting the blocking group R of these hydroxyls e(R eWith aforementioned equivalent in meaning.) deprotection, obtain the reaction of The compounds of this invention (I-4a).In the deprotection of midbody (XIII-2), so long as usually use in the deprotection of blocking group, not special restriction can be with whole blocking groups once or the substep deprotection.R for example cFor methoxymethyl etc. through acid can deprotection blocking group, R dDuring for tertbutyloxycarbonyl, can be through acid while deprotection.The acid of this moment has mineral acid such as hydrochloric acid or trifluoracetic acid etc.And as reaction conditions, can enumerate in ether series solvent, water or their mixed solvents such as alcohol property solvent such as ethanol or THF, carry out about 10 minutes～12 hours under～80 ℃ down ice-cold.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
13) in the The compounds of this invention, the R in the general formula (I) is that Wasserstoffatoms, Y are CH 2CH 2, R 1, carbonatoms substituted for halogen atom is 1～4 alkyl, R 2Be methylol, R 3And R 4The compound of representing for Wasserstoffatoms (I-5a) is also can be synthetic through following circuit (XIV).
[Chemical formula 1 6]
Circuit (XIV)
Figure S2006800472557D00301
(in the formula, R 1, carbonatoms substituted for halogen atom is 1～4 alkyl, and X is Sauerstoffatom or sulphur atom, X fBe leavings group, R gFor blocking group or-(CH 2) nCH 3, R 2Be methylol, n and aforementioned equivalent in meaning.)
X fThe leavings group of expression is so long as the group that can leave away during according to alkoxide or the anionic replacement(metathesis)reaction of mercaptan, not special restriction.Halogen atom (concrete have fluorine atom etc.), tosyloxy etc. are for example arranged.R in the formula gDuring for blocking group, R gSo long as the group of protection phenylol or thiol group, not special restriction.As R gExample, X is alkyl (methyl etc.), aralkyl (benzyl etc.) during for Sauerstoffatom, form the blocking group (methoxymethyl or ethoxyethyl group etc.) of acetal etc.And, when X is sulphur atom, alkyl (methyl etc.), aralkyl (4-methoxy-benzyl etc.) arranged, form the blocking group (methoxymethyl or phenyl sulphomethyl, acetamidomethyl etc.) of thioacetal etc.
First step is with on 4, having leavings group X fMethyl phenyl ketone (XIV-1) and alcohol or mercaptan (XIV-2) condensation, obtain the reaction of midbody (XIV-3).This step is at N, in the ether series solvents such as dinethylformamide or DMSO 99.8MIN. isopolarity solvent or THF, in the presence of alkali, carries out.As alkali, can use mineral alkalis, 1 such as sodium hydride or Pottasium Hydroxide, 8-diazonium two ring [5.4.0] 11 carbon-organic basess such as 7-alkene carry out.As reaction conditions, can enumerate under ice-cold following about～100 ℃ and carry out about 10 minutes～10 hours.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care through distillation, silica gel column chromatography, recrystallize etc. as required, can obtain title product.
Second step is the ethanoyl of bromination midbody (XIV-3), obtains the reaction of bromination phenacyl-body (XIV-4).This step can be carried out in pure series solvents such as ether series solvent, methyl alcohol such as halogen series solvent 、 diox such as chloroform or acetic acid equal solvent.As the reagent of bromination, bromine, pyridine tribromide, phenyltrimethyammonium tribromide etc. can have been enumerated.As reaction conditions, can enumerate under ice-cold following about～60 ℃ and carry out about 30 minutes～10 hours.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
Third step is condensation midbody (XIV-4) and ethanamide ethyl malonate, obtains the reaction of midbody (XIV-5).This step is at N, in the ether series solvents such as dinethylformamide or DMSO 99.8MIN. isopolarity solvent or THF, in the presence of alkali, carries out.As alkali, can use mineral alkalis such as sodium hydride, Pottasium Hydroxide, tert.-butoxy potassium to carry out.As reaction conditions, enumerated under ice-cold following about～50 ℃ and carried out about 10 minutes～5 hours.After the reaction,, make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product according to usual method stopped reaction, extraction, cleaning, drying, removal solvent etc.
The 4th step is that the carbonyl reduction with midbody (XIV-5) becomes methylene radical, obtains the reaction of midbody (XIV-6).As reductive agent, can use the combination of trialkyl silane and trifluoroacetic combination or trialkyl silane and titanium tetrachloride etc., also can be 1, carry out in the halogen series solvents such as 2-ethylene dichloride or under solvent-free.As reaction conditions, can enumerate at ice-cold time～reflux temperature and carry out about 1～48 hour.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
The midbody that obtains can be incorporated in the The compounds of this invention (I-5a) through known method (for example journal of medicinal chemistry the 43rd volume (2000) 2946-2961 page or leaf).
14) in the The compounds of this invention, the R in the general formula (I) 3And R 4One of any or R 3And R 4Both are that carbonatoms is that the compound (I-6a) that 1～4 alkyl is represented comes synthetic through following circuit (XV).
[Chemical formula 1 7]
Circuit (XV)
Figure S2006800472557D00311
(in the formula, R is Wasserstoffatoms or P (=O) (OH) 2, X is Sauerstoffatom or sulphur atom, R 1, carbonatoms substituted for halogen atom is 1～4 alkyl or cyanic acid, R 2For can be by hydroxyl substituted or can be 1～4 alkyl by the substituted carbonatoms of halogen atom, R 3And R 4One of any or both be that carbonatoms is 1～4 alkyl, Y is CH 2CH 2Or CH=CH, n and aforementioned equivalent in meaning.)
This step is through the aminoalkyl groupization with the compound that has primary amino in the The compounds of this invention (XV-1), the step of synthetic The compounds of this invention (1-6a).In should synthesizing, can use the alkylated reaction of the amine of reductive ammoxidation or haloalkyl and use alkali.When using the reductive ammoxidation, have and R 3Or R 4The aldehyde of same carbon atoms number and compound (XV-1) use the reaction of reductive agents such as Peng Qinghuana, hydroboration cyanic acid sodium, hydroboration sodium triacetoxy in halogen series solvents such as pure series solvent such as methyl alcohol or ethylene dichloride, obtain title product.In the reduction, can use hydrogen and catalyzer such as La Nai nickel or platinum oxide to carry out.And this reaction can be carried out the generation and the reduction reaction of Schiff's base successively.In this reductive ammoxidation, can add acid such as acetic acid as reaction promotor.As reaction conditions, can enumerate under ice-cold following about～50 ℃ and carry out about 30 minutes～10 hours.After the reaction, according to the usual method stopped reaction, filter, extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.R 3And R 4During for methyl, also can use formic acid and reductive agents such as formaldehyde or formaldehyde and sodium cyanoborohydride, use the methylation reaction of Eschweiler-Clarke.
15) in the The compounds of this invention, the R in the general formula (I) is a Wasserstoffatoms, and Y is CH=CH, R 1, carbonatoms substituted for halogen atom is 1～4 alkyl or cyanic acid, R 3And R 4For the compound (I-7a) that Wasserstoffatoms is represented can be synthetic through following circuit (XVI).
[Chemical formula 1 8]
Circuit (XVI)
Figure S2006800472557D00321
(in the formula, X is Sauerstoffatom or sulphur atom, R 1, carbonatoms substituted for halogen atom is 1～4 alkyl or cyanic acid, R 2For can be by hydroxyl substituted or can be substituted by halogen atom, carbonatoms is 1～4 alkyl, R cAnd R dBe blocking group, R gFor blocking group or-(CH 2) nCH 3, X aAnd X bBe leavings group, X gFor containing the leavings group of phosphorus, n and aforementioned equivalent in meaning.)
R in the formula cSo long as the group of protection hydroxyl, not special restriction.For example can enumerate the substituting group (being specially methoxyl methyl, THP trtrahydropyranyl etc.) of acyl group (preferred carbonatoms is about 2～4, is specially ethanoyl etc.), trialkylsilkl (being specially trimethyl silyl etc.), benzyl or formation acetal compound.R 2When having hydroxyl, this blocking group R e(as R eConcrete and R cThe same) can and R cIn conjunction with, form the cyclic acetal.R in the formula dThe blocking group of expression is so long as the amino group of protection, not restriction especially.Acyl group (preferred carbonatoms is about 2～4, is specially ethanoyl etc.), carbamate (tert-butoxycarbonyl or benzyloxycarbonyl etc. are specifically arranged) etc. for example can have been enumerated.R in the formula gDuring the expression blocking group, R gSo long as the group of protection phenolic group or thiol group, not special restriction.As R gExample, at X alkyl (methyl etc.), aralkyl (4-methoxy-benzyl etc.) arranged during for Sauerstoffatom, form the blocking group (methoxymethyl or ethoxyethyl group etc.) of acetal etc.And, when X is sulphur atom, alkyl (methyl etc.), aralkyl (4-methoxy-benzyl etc.) arranged, form the blocking group (methoxymethyl or phenyl sulphomethyl, acetamidomethyl etc.) of thioacetal etc.And X aShown leavings group is so long as through alkoxide ion (R g-O -) or thiolate (R g-S -) replacement(metathesis)reaction the time group that can break away from, not special restriction.Halogen atom (fluorine atom etc. is specifically arranged), tosyloxy etc. are for example arranged.X bThe leavings group of expression be so long as can slough when the reaction of midbody (XVI-5) and phosphorus compound, then and do not hinder the group of reaction during aldehyde (II-6) reaction, do not limit especially.Halogen atom (being specially iodine atom, bromine atoms, chlorine atom etc.), methanesulfonyloxy group, tosyloxy etc. are for example arranged.X gThe leavings group that contains phosphorus of expression can have been enumerated P (C 6H 5) 3Or P (O) (OR h) 2(R hThe expression carbonatoms is 1～4 alkyl).
First step is through will on 4, having leavings group X aTRIMETHOXY BENZOIC ACID (FOR MANUFACTURING OF T.M. (XVI-1) and the condensation of ethanol or mercaptan (XVI-2), obtain the reaction of midbody (XVI-3).This step is at N, in the ether series solvents such as dinethylformamide or DMSO 99.8MIN. isopolarity solvent or THF, in the presence of alkali, carries out.As alkali, can use alkoxide, 1 such as mineral alkalis such as sodium hydride, Pottasium Hydroxide, salt of wormwood, potassium tert.-butoxy thing, 8-diazonium two ring [5.4.0] 11 carbon-organic basess such as 7-alkene carry out.As reaction conditions, can enumerate under ice-cold following about～80 ℃ and carry out about 30 minutes～24 hours.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
Second step is the carboxyl of reduction midbody (XVI-3), and acquisition has the reaction of the midbody (XVI-4) of hydroxyl.As the reagent that in reduction, uses; So long as normally used reagent; Not special restriction can be enumerated boron cpds such as metallic hydrogen coordination compound, diborane such as basic metal such as sodium or two (2-methoxy ethoxy) the aluminium sodium of metal hydrides such as alkaline-earth metal, diisobutylaluminium hydride, lithium aluminum hydride or hydrogenation, use the contact hydrogenation of homogeneous phase or heterogeneous catalyst etc.Reaction conditions is selected suitable temperature and time according to the original reagent of going back that uses.Concrete, can enumerate in ether series solvents such as THF under-30 ℃～reflux temperature carries out about 10 minutes～12 hours, through diborane, lithium aluminium hydride reduction; In inert solvents such as toluene, carry out about 30 minutes～24 hours under～50 ℃ down ice-cold, through two (2-methoxy ethoxy) the aluminium sodium reductions of hydrogenation etc.After the reaction,, make with extra care through distillation, silica gel column chromatography, recrystallize etc. as required, can obtain title product according to usual method stopped reaction, extraction, cleaning, drying, removal solvent etc.
Third step is that the hydroxyl with midbody (XVI-4) is transformed into leavings group X bReaction.As reagent, so long as convert alcohol hydroxyl group to X bReagent, not special restriction.X bThe reagent that uses during for halogen atom can be enumerated the mineral acid, phosphorus tribromide, phosphorus pentabromide, phosphorus trichloride, phosphorus pentachloride, iodine, bromine, chlorine, halo thionyl, alpha-halogen enamine of the combination, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI and so on of N-chlorosuccinimide, N-bromosuccinimide, tetracol phenixin or they and reaction auxiliarys such as triphenylphosphine, alkali etc.As reaction conditions, can enumerate in organic solvents such as ether series solvent such as halogen series solvents such as methylene dichloride or THF, carrying out about 10 minutes～6 hours under-30 ℃～130 ℃.In addition, when using mineral acid, also can in two coating systems of organic solvent such as the aqueous solution or toluene and water, react.X bThe reagent that uses during for sulfonyloxy has the combination of chloro alkylsulfonyls such as methyl chloride alkylsulfonyl or chlorotoluene alkylsulfonyl and organic basess such as triethylamine or pyridine.As reaction conditions, can enumerate in organic solvents such as ether series solvent such as halogen series solvents such as methylene dichloride or THF, carrying out about 5 minutes～3 hours under-30 ℃～50 ℃.After the reaction,, extract, clean according to the usual method stopped reaction, dry, remove solvent etc., make with extra care through distillation, silica gel column chromatography, recrystallize etc. as required, can obtain title product.
The 4th step is with having leavings group X bThe reaction of midbody (XVI-5) and phosphorus compound, obtain to have the leavings group X that contains phosphorus gThe reaction of midbody (XVI-6).X gBe P (C 6H 5) 3The time, midbody (XVI-6) obtains through midbody (XVI-5) and triphenylphosphine reaction.As reaction conditions, can enumerate in inert solvents such as diethyl ether, benzene, toluene, at room temperature～reflux temperature carries out about 30 minutes～12 hours.After the reaction, carry out as required solvent heat up in a steamer, cool off, add insoluble solvents such as Di Iso Propyl Ether or hexane after, the solid that leaching is separated out can obtain title product.X gBe P (O) (OR h) 2(R hWith aforementioned equivalent in meaning.) time, the Arbuzov reaction that midbody (XVI-6) can pass through midbody (XVI-5) and triethyl-phosphite obtains.As reaction conditions, in not using inert solvents such as solvent or YLENE, carrying out about 30 minutes～12 hours under 100 ℃～170 ℃.After the reaction,, can obtain title product through carrying out heating up in a steamer or distilling of superfluous triethyl-phosphite.
The 5th step is with midbody that contains phosphorus (XVI-6) and synthetic aldehyde (II-6) condensation in addition, obtains the reaction of alkene body (XVI-7).X gBe P (C 6H 5) 3The time, the condition of using common Wittig to react.For example have in ether series solvents such as THF, use alkali such as sodium hydride or potassium tert.-butoxy thing, under-30 ℃～reflux temperature carries out about 30 minutes～12 hours.In the aprotic polar solvent, under salt-free condition, react, preferentially obtain the Z body, through the improved method of Schlosser, also can preferentially obtain the E body.After the reaction,, make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product according to usual method stopped reaction, extraction, cleaning, drying, removal solvent etc.X gBe P (O) (OR h) 2(R hWith aforementioned equivalent in meaning.) time, the condition of using common Horner-Wadsworth-Emmons to react.For example have in ether series solvents such as hydrocarbon solvent such as benzene or THF, use sodium hydride or alkali such as tert.-butoxy potassium, hexamethyldisilazane base lithium, under-20 ℃～reflux temperature carries out about 30 minutes～12 hours.Alkene can preferentially obtain the E body.After the reaction,, make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product according to usual method stopped reaction, extraction, cleaning, drying, removal solvent etc.
The 6th step is the blocking group R at midbody (XVI-7) c, R dAnd R 2When having hydroxyl, through to protecting the blocking group R of these groups e(R eWith aforementioned equivalent in meaning.) deprotection, obtain the reaction of The compounds of this invention (I-7a).As the condition of using, so long as in the deprotection of blocking group usually, use, not special restriction, all blocking groups can be once or the substep deprotection.R for example cBe blocking group, the R that forms acetal dWhen being tertbutyloxycarbonyl, can be through acid while deprotection.As the acid of this moment, mineral acid such as hydrochloric acid or trifluoracetic acid etc. can have been enumerated.And as reaction conditions, have in ether series solvent, water or their mixed solvents such as alcohol property solvent such as ethanol or THF, carry out about 10 minutes～12 hours under～80 ℃ down ice-cold.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.R gDuring the expression blocking group, at blocking group R cAnd R dDeprotection before, can carry out R gDeprotection and the alkylation of thus obtained phenol or mercaptan.R gDeprotection in the condition used, so long as the condition of in the deprotection of blocking group usually, using, not special restriction, for example R gDuring for the 4-methoxy-benzyl, through 2,3-two chloro-5,6-dicyano-1, the oxidizing reaction of 4-benzoquinones (DDQ) etc., R gDuring for allyl group, palladium compound reacts as catalyzer.The reagent that uses in the alkylation process as phenolic hydroxyl group that has at the compound that obtains or thiol group can be enumerated the combination of alkylating agent such as haloalkyl and mineral alkalis such as salt of wormwood or sodium hydride.As reaction conditions, can enumerate at N, in the ether series solvents such as dinethylformamide isopolarity solvent or THF, under ice-cold following～80 ℃, carry out about 10 minutes～12 hours.And, in the alkylation of phenolic hydroxyl group, also can make to use up and prolong reaction.
16) R in the general formula (I) is Wasserstoffatoms, R 1The compound of representing for difluoromethyl (I-8a) is synthetic through following circuit (XVII).
[Chemical formula 1 9]
Circuit (XVII)
Figure S2006800472557D00361
(in the formula, X is Sauerstoffatom or sulphur atom, and Y is CH 2CH 2Or CH=CH, R 2Be can be by hydroxyl substituted or can be substituted by halogen atom, carbonatoms is 1～4 alkyl, R cAnd R dBe blocking group, R gBe blocking group or-(CH 2) nCH 3, X aAnd X cBe leavings group, n and aforementioned equivalent in meaning.)
R in the formula c, R d, R g, X a, X cObject lesson and aforementioned equivalent in meaning.
First step is through having leavings group X aRaw material (XVII-1) and alcohol or mercaptan (XVII-2) condensation, obtain the reaction of midbody (XVII-3).This step is at N, in the ether series solvents such as dinethylformamide or DMSO 99.8MIN. isopolarity solvent or THF, in the presence of alkali, carries out.As alkali, can use alkoxide, 1 such as mineral alkalis such as sodium hydride, Pottasium Hydroxide, salt of wormwood, tert.-butoxy potassium, 8-diazonium two ring [5.4.0] 11 carbon-organic basess such as 7-alkene carry out.As reaction conditions, can enumerate under ice-cold following about～80 ℃ and carry out about 30 minutes～24 hours.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.And, the leavings group X of compound (XVII-1) aBe phenolic hydroxyl group or mercaptan can be used as raw material, at this moment, this first step is the alkylation of phenolic hydroxyl group or mercaptan.As the reagent that uses in this alkylation, can enumerate the alkylating agent of haloalkyl etc. and the combination of mineral alkalis such as salt of wormwood or sodium hydride.As reaction conditions, can enumerate at N, in the ether series solvents such as dinethylformamide isopolarity solvent or THF, under ice-cold following～80 ℃, carry out about 10 minutes～12 hours.And, in the alkylation of phenolic hydroxyl group, also can make to use up and prolong reaction.
Second step is the formyl radical of fluorinated intermediates (XVII-3), and acquisition has the reaction of the midbody (XVII-4) of difluoromethyl.This step is in halogen series solvents such as methylene dichloride, and use three is fluoridized fluorizating agents such as diethylamino sulphur (DAST) or xenon difluoride and carried out.In this fluoridation, replace using separately fluorizating agent, in the presence of fluoride ions such as TBuA fluorochemical, N-iodate succinimide etc. also can as oxygenant.As reaction conditions, can enumerate under ice-cold following about～50 ℃ and carry out about 1～24 hour.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care through distillation, silica gel column chromatography, recrystallize etc. as required, can obtain title product.
The third step is performed by the condensation reaction of the intermediate header Yuan (XVII-4) and intermediates (IV-3), containing a triple bond is obtained intermediate (XVII-5) reaction.Tetrakis triphenylphosphine palladium (0), three (dibenzalacetones), two palladiums (0), two (acetonitrile) palladium palladium compounds such as (II) of dichloro can have been enumerated as the catalyzer that uses.And, also can add copper compound, 2-dicyclohexyl phosphino-s-2 ' such as mineral alkali, cupric iodide or cupric bromide such as organic bases such as triethylamine or ammonia, additives such as phosphine compound such as 4 ', 6 '-tri isopropyl biphenyl base in order to promote reaction.As reaction conditions, can enumerate in ether series solvent, acetonitrile or hydrocarbon solvents such as N isopolarity solvent or benzene such as THF Huo diox, in ice-cold refluxed about 30 minutes～24 hours.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
The 4th step is the triple bond of reduction midbody (XVII-5), obtains the reaction of midbody (XVII-6).As Y is CH 2CH 2The time reagent that uses; So long as the reagent that in the reduction of common unsaturated carbon bond, uses; Not restriction for example can be enumerated to use and carry the palladium gac or draw nickel how, carry the contact hydrogenation of heterogeneous catalyst such as palladium gac quadrol complex body, rhodium coordination compound homogeneous catalysts such as (chloro three (triphenylphosphine) rhodiums (I) etc.).As reaction conditions, can enumerate in hydrocarbon solvents such as ether series solvent such as pure series solvent 、 dioxs such as ethanol or toluene, under 1～20 atmospheric hydrogen-pressure, ice-cold down～reflux temperature carries out 30 minutes～1 time-of-week.In addition, according to stability of speed of response or compound etc., can in reaction solution, add alkali such as acid such as acetic acid or triethylamine.After the reaction, according to usual method filter, extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.On the other hand; The reaction of using during for CH=CH as Y can be enumerated the hydrogenation that contacts that in the presence of the active catalyzer of adjusting such as various coordination compoundes of Lindlar catalyzer, nickel-graphite-quadrol coordination compound, diolefin and phosphine compound and rhodium, carries out.And, use and also can by the reduction reaction of metal hydrides such as diisobutylaluminium hydride.After the reaction, according to usual method filter, extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
The 5th step is through to midbody (XVII-6) deprotection, obtains the reaction of The compounds of this invention (I-8a).R c, R dAnd R 2When having hydroxyl, to protecting the blocking group R of these groups e(R eWith aforementioned equivalent in meaning.) deprotection in, so long as usually use in the deprotection of blocking group, not special restriction, all blocking groups can be once or the substep deprotection.R for example cAnd R eIn conjunction with forming cyclic acetal, R dDuring for tertbutyloxycarbonyl, the acid that can pass through catalytic amount is then carried out R to cyclic acetal deprotection under stronger acidic conditions dDeprotection.The condition of using in the deprotection of acetal at this moment; Can enumerate in the mixing solutions of ethanol property solvent such as methyl alcohol or ethanol property solvent and other organic solvent; Use the hydrochloric acid or the toluenesulphonic acids of catalytic amount, under ice-cold following～80 ℃, carry out about 30 minutes～12 hours.On the other hand, as the R that carries out below the deprotection of acetal dThe condition of deprotection, mineral acids such as using the above hydrochloric acid of equivalent or trifluoracetic acid etc. are arranged, in ether series solvent, water or their mixed solvents such as alcohol property solvent such as ethanol or THF, carry out about 10 minutes～12 hours under～80 ℃ down ice-cold.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.R gDuring the expression blocking group, at blocking group R cAnd R dDeprotection before, carry out R gDeprotection and the alkylation of thus obtained phenol or mercaptan.As R gDeprotection in the condition used, so long as the condition of in the deprotection of blocking group usually, using, not special restriction, for example R g3-two chloro-5,6-dicyano-1, the oxidizing reaction of 4-benzoquinones (DDQ) etc., R during for the 4-methoxy-benzyl, have been enumerated through 2 gWhen being allyl group, have the reaction of palladium compound as catalyzer.The reagent that uses in the phenolic hydroxyl group that has as the compound that obtains or the alkylation of thiol group can be enumerated the combination of alkylating agent such as haloalkyl and mineral alkalis such as salt of wormwood or sodium hydride.As reaction conditions, can enumerate at N, in the ether series solvents such as dinethylformamide isopolarity solvent or THF, under ice-cold following～80 ℃, carry out about 10 minutes～12 hours.And, in the alkylation of phenolic hydroxyl group, also can make to use up and prolong reaction.
17) R in the general formula (I) is Wasserstoffatoms, R 1The compound of representing for methyl fluoride (I-9a) is to synthesize through following circuit (XVIII).
[Chemical formula 2 0]
Circuit (XVIII)
Figure S2006800472557D00391
(in the formula, X is Sauerstoffatom or sulphur atom, and Y is CH 2CH 2Or CH=CH, R 2Be can be by hydroxyl substituted or can be substituted by halogen atom, carbonatoms is 1～4 alkyl, R c, R dAnd R iBe blocking group, X aAnd X cBe leavings group, n and aforementioned equivalent in meaning.)
R in the formula c, R d, X a, X cObject lesson and above-mentioned equivalent in meaning.As the R in the formula iThe blocking group of expression, so long as the group of protection hydroxyl, not special restriction.Trialkylsilkl (specifically being t-butyldimethylsilyl etc.) is for example arranged.
First step is through having leavings group X aRaw material (XVIII-1) and alcohol or mercaptan (XVIII-2) condensation, obtain the reaction of midbody (XVIII-3).This step is at N, in the ether series solvents such as dinethylformamide or DMSO 99.8MIN. isopolarity solvent or THF, in the presence of alkali, carries out.As alkali, can use alkoxide, 1 such as mineral alkalis such as sodium hydride, Pottasium Hydroxide, salt of wormwood, tert.-butoxy potassium, 8-diazonium two ring [5.4.0] 11 carbon-organic basess such as 7-alkene carry out.As reaction conditions, can enumerate under ice-cold following about～80 ℃ and carry out about 30 minutes～24 hours.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.And, can be with the leavings group X of compound (XVIII-1) aFor the material of phenolic hydroxyl group or mercaptan as raw material, at this moment, this first step is with phenolic hydroxyl group or mercaptan alkylation.As the reagent that in this alkylation, uses, can enumerate the combination of alkylating agents such as haloalkyl and mineral alkalis such as salt of wormwood or sodium hydride.As reaction conditions, enumerated at N, in the ether series solvents such as dinethylformamide isopolarity solvent or THF, under ice-cold following～80 ℃, carry out about 10 minutes～12 hours.And, in the alkylation of phenolic hydroxyl group, also can make to use up and prolong reaction.
Second step is with the reduction of the formyl radical of midbody (XVIII-3), process methylol after, introduce blocking group R iReaction.As the reagent that in the reduction of formyl radical, uses; So long as normally used reagent; Not special restriction can be enumerated metallic hydrogen coordination compoundes such as metal hydride, lithium aluminum hydride or Peng Qinghuana such as diisobutylaluminium hydride, use the contact hydrogenation of homogeneous phase or heterogeneous catalyst etc.Reaction conditions is selected suitable temperature and time according to the original reagent of going back that uses.Concrete, can enumerate in ether series solvents such as THF and carry out under-30 ℃～room temperature about 10 minutes～3 hours, by lithium aluminum hydride, lithium borohydride reduction; In the mixed solvent of pure series solvent such as ethanol or ether series solvents such as pure series solvent and THF, ice-cold down～carry out about 10 minutes～3 hours under the room temperature, through Peng Qinghuana or hydroboration calcium reduction etc.After the reaction,, make with extra care through distillation, silica gel column chromatography, recrystallize etc. as required, can obtain title product according to usual method stopped reaction, extraction, cleaning, drying, removal solvent etc.At blocking group R iIntroducing in, use the introducing reaction of common blocking group.At R iIn when using trialkylsilkl, use silylating agents such as tertiary butyl dimethyl-chlorosilane as reagent, can add alkali such as imidazoles or triethylamine as reaction promotor.After the reaction,, make with extra care through distillation, silica gel column chromatography, recrystallize etc. as required, can obtain title product according to usual method stopped reaction, extraction, cleaning, drying, removal solvent etc.
The third step is performed by the condensation reaction of the intermediate header Yuan (XVIII-4) and intermediates (IV-3), containing a triple bond is obtained intermediate (XVIII-5) reaction.As the catalyzer that uses, tetrakis triphenylphosphine palladium (0), three (dibenzalacetones), two palladiums (0), two (acetonitrile) palladium palladium compounds such as (II) of dichloro can have been enumerated.And, can add copper compound, 2-dicyclohexyl phosphino-s-2 ' such as mineral alkali, cupric iodide or cupric bromide such as organic bases such as triethylamine or ammonia, additives such as phosphine compound such as 4 ', 6 '-tri isopropyl biphenyl base in order to promote reaction.As reaction conditions, can enumerate in ether series solvents such as THF Huo diox, acetonitrile or hydrocarbon solvents such as N isopolarity solvent or benzene, carry out about 30 minutes～24 hours at ice-cold time～reflux temperature.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
The 4th step is the triple bond of reduction midbody (XVIII-5), obtains the reaction of midbody (XVIII-6).As Y is CH 2CH 2The time reagent that uses; So long as the reagent that uses in the reduction of common unsaturated carbon bond; Not restriction for example has to use and carries the palladium gac or draw nickel how, carry the contact hydrogenation of heterogeneous catalyst such as palladium gac quadrol complex body, rhodium coordination compound homogeneous catalysts such as (chloro three (triphenylphosphine) rhodiums (I) etc.).As reaction conditions, can enumerate in hydrocarbon solvents such as ether series solvent such as pure series solvent 、 dioxs such as ethanol or toluene, under 1～20 atmospheric hydrogen-pressure, ice-cold down～reflux temperature carries out 30 minutes～1 time-of-week.In addition, according to stability of speed of response or compound etc., also can in reaction solution, add alkali such as acid such as acetic acid or triethylamine.After the reaction, according to usual method filter, extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.On the other hand, the reaction of using when being CH=CH as Y, the various coordination compoundes of Lindlar catalyzer, nickel-graphite-quadrol coordination compound, diene and phosphine, rhodium etc. regulate active catalyzer in the presence of, contact hydrogenation.And also can use reduction reaction through metal hydrides such as diisobutylaluminium hydrides.After the reaction, according to usual method filter, extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
The 5th step is the R to compound (XVIII-6) iDeprotection, the hydroxyl of the compound through fluoridizing acquisition, synthetic step of fluoridizing object (XVIII-7).Blocking group R iDeprotection can use common deprotection reaction to carry out.As R iThe reagent that uses when being trialkylsilkl can use fluorine cpd such as TBuA fluorochemical.As the condition of this reaction, can enumerate in ether series solvents such as THF, carry out about 30 minutes～24 hours at ice-cold time～reflux temperature.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care through distillation, silica gel column chromatography, recrystallize etc. as required, can obtain title product.As the reagent that uses in ensuing the fluoridizing, diethylaminosulfur trifluoride (DAST) or 2 can have been enumerated, 2-two fluoro-1,3-methylimidazole alkane (DFI) etc.This step is in hydrocarbon solvents such as halogen series solvents such as methylene dichloride or hexane, to react.As reaction conditions, can enumerate under-78 ℃～room temperature and carry out about 30 minutes～12 hours.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.And after this step can be transformed into corresponding sulphonate body with hydroxyl, the method for the effect through fluoride ion was carried out.When for example using p-toluenesulfonyl fluorochemical and TBuA fluorochemical (TBAF), in ether series solvents such as THF, under room temperature～80 ℃, react about 1 hour～24 hours.Can add dewatering agents such as molecular sieve in this reaction.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.In addition, at R iDuring for trialkylsilkl, do not carry out R iDeprotection also can fluoridize.
The 6th step is through to midbody (XVIII-7) deprotection, obtains the reaction of The compounds of this invention (I-9a).R c, R dAnd R 2When having hydroxyl, at the blocking group R of these groups of protection e(R eWith aforementioned equivalent in meaning.) deprotection in, so long as in the deprotection of common blocking group, use, not special restriction, all blocking groups can be once or the substep deprotection.R for example cAnd R eIn conjunction with forming cyclic acetal, R dDuring for tertbutyloxycarbonyl, next the acid through catalytic amount through using stronger acidic conditions, carry out R to cyclic acetal deprotection dDeprotection.The condition of using in the deprotection as acetal this moment; Can enumerate in the mixing solutions of ethanol property solvent such as methyl alcohol or ethanol property solvent and other organic solvents; Use the hydrochloric acid or the toluenesulphonic acids of catalytic amount, under ice-cold following～80 ℃, carry out about 30 minutes～12 hours.On the other hand, the then R that carries out of the deprotection of acetal dThe condition of deprotection; Can enumerate mineral acids such as using the above hydrochloric acid of equivalent or trifluoracetic acid etc.; In ether series solvent, water or their mixed solvents such as ethanol property solvent such as ethanol or THF, ice-cold down～carry out about 10 minutes～5 hours under the room temperature.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.And, in reaction soln, add the low solvent of solvability of Di Iso Propyl Ether etc., the title product of can leaching separating out.
18) in the The compounds of this invention, the R in the general formula (I) is P (=O) (OH) 2, R 3And R 4The compound of representing for Wasserstoffatoms (I-10a) is through following circuit (XIX) synthetic.
[Chemical formula 2 1]
Circuit (XIX)
(in the formula, X is Sauerstoffatom or sulphur atom, and Y is CH 2CH 2Or CH=CH, R 1Be that halogen atom is substituted, carbonatoms is 1～4 alkyl or cyanic acid, R 2Be can be by hydroxyl substituted or can be 1～4 alkyl by the substituted carbonatoms of halogen atom, R dAnd R jBe blocking group, n and aforementioned equivalent in meaning.)
R in the formula dWith aforesaid equivalent in meaning.The R of compound (XIX-2) 2On when containing hydroxyl, this hydroxyl can be by blocking group R e(R eWith aforementioned equivalent in meaning.) protection.And R 2When being shielded methylol or hydroxyethyl, this blocking group R eBe R dOr R dCombine with nitrogen-atoms, through forming following such ring compound (XIX-2 ', XIX-2 ")
[Chemical formula 2 2]
Figure S2006800472557D00431
(in the formula, p is 1 or 2, and other each symbols and circuit (XIX) are equivalent in meaning.), also can protect should amino and hydroxyl.R in the formula jThe blocking group of expression is so long as can protect phosphate, not special restriction.Alkyl (preferred carbonatoms is about 1～6, is specially the tertiary butyl etc.), benzyl, phenyl etc. are for example arranged.
First step is that R is the amino of the compound (XIX-1) of Wasserstoffatoms in the The compounds of this invention through protecting, the step of synthesizing amino protective (XIX-2).This step can be used common amido protecting to react to carry out.Concrete, as blocking group (R d) when using acyl group, carbalkoxy or carbobenzoxy-(Cbz) etc., this step can be carried out in alcohol such as methyl alcohol or in two coating systems of organic solvents such as water and vinyl acetic monomer or chloroform or the mixed solution.As the reagent that uses, acid anhydrides such as sour muriate such as chloro ethanoyl or chloro carbobenzoxy, acetic anhydride or di-tert-butyl dicarbonic acid ester can have been enumerated.As the reaction promotor in this reaction, can use mineral alkalis such as organic basess such as triethylamine or sodium hydrogencarbonate.As reaction conditions, can enumerate under ice-cold following～50 ℃ and carry out about 30 minutes～24 hours.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.And, as De oxazoline shown in the general formula (XIX-2 '), amino and R 2In the hydroxyl that comprises when being protected simultaneously, this step can be at acetonitrile or N, in the hydrocarbon solvents such as halogen series solvent such as dinethylformamide isopolarity solvent, methylene dichloride or toluene, uses the ortho-acetate as reagent to react.And in order to promote reaction, can add N, acid such as alkali such as N-diisopropylethylamine or tosic acid.As reaction conditions, can enumerate at room temperature～reflux temperature carries out about 30 minutes～12 hours.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
Second step is with amido protecting body (XIX-2) and phosphorylation agent (for example phosphoric acid muriate, phosphoramidite and oxygenant, tetra-sodium tetrabenzyl ester etc.) reaction, the step of synthetic phosphorylation body (XIX-3).When using tetra-sodium tetrabenzyl ester as phosphorylation agent, this step is under non-water condition, in preferred toluene, methylene dichloride, their organic solvents such as mixed solvent, uses additive (for example silver suboxide, iodate four just own ammonium etc.) to carry out.As reaction conditions, can enumerate under ice-cold following～50 ℃ and carry out about 5～24 hours.After the reaction, according to usual method filter, extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.And this reaction is based on known method with common phosphorylation agent (phosphoric acid muriate and alkali, phosphoramidite and oxygenant etc.) reaction, also can synthesize.When for example using phosphoramidite and oxygenant; In ether series solvent, acetonitrile isopolarity solvent or their mixed solvents such as halogen series solvent, THF such as methylene dichloride; Use phosphoramidites such as di-t-butyl diisopropylphosphoramidite, reacted about 10 minutes～5 hours down at ice-cold following～50 ℃.Can add reaction promotors such as 1H-tetrazolium in this reaction.Then in the oxidizing reaction of the phosphorus of this phosphorylation, between using-inorganic peroxides such as organo-peroxide such as chloro perbenzoic acid or tertbutyl peroxide or hydrogen peroxide.Reaction is under ice-cold following～50 ℃, to carry out about 3 minutes～1 hour.After the reaction, through usual method extract, clean, dry, remove solvent etc., make with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.
Third step is the step from phosphorylation body (XIX-3) preparation The compounds of this invention (I-10a).This step can use common deprotection reaction to carry out.Concrete, can carry out hydrogenation and divide Lewis acids such as acid such as separating, use hydrochloric acid or trifluoracetic acid, bromination trimethyl silyl and carry out.Use hydrogenation to divide when separating in this reaction, this step is in alcohol property solvents such as methyl alcohol, uses catalyzer such as carrying the palladium gac, under atmosphere of hydrogen gas, carries out.As reaction conditions, can enumerate under room temperature～60 ℃ and carry out about 1～24 hour.Reaction solution filters, concentrates etc. according to usual method, is made with extra care by silica gel column chromatography, recrystallize etc. as required, can obtain title product.And the reaction conditions when in this reaction, using acid can be enumerated in the mixed solvent of alcohol property solvent such as ethanol or they and water, under room temperature～100 ℃, carries out about 30 minutes～12 hours.After the reaction, in water, drop into reaction solution after, the title product that leaching is separated out, perhaps extract, clean, dry, remove solvent etc., make with extra care by silica gel chromatography or crystallization etc. as required, can obtain title product.And in the The compounds of this invention, the R in the general formula (I) is P (=O) (OH) 2, R 3Or R 4One of any for carbonatoms be that 1～4 alkylate also can adopt with the same method of above-mentioned circuit (XIX) and synthesizes.On the other hand, the R in general formula (I) is P (=O) (OH) 2, R 3And R 4Be the blocking group R that the compound of 1～4 alkyl can not adopt the amino that circuit (XIX) uses for carbonatoms simultaneously d, through synthesizing with the identical method of circuit (XIX).
The compounds of this invention is as required, through in the appropriate solvent (water, ethanol, ether etc.) with the processing of acid, can process acid salt.And the The compounds of this invention of acquisition is handled through water, water-containing solvent or other solvents (for example ethanol etc.), can process hydrate or solvate.
The compounds of this invention is useful for treating or preventing following disease: the treatment or the prevention of auto-immune disease (for example rheumatic arthritis, multiple sclerosis, encephalomyelitis, systemic lupus erythematosus, systemic lupus erythematosus, nephrotic syndrome, psoriasis, type i diabetes etc.); To the opposing of the transplanting (for example comprising transplanting, the xenotransplantation of heart, kidney, liver, lung, marrow, cornea, pancreas, small intestine, four limbs, muscle, nerve, fatty marrow, duodenum, skin, islet cells etc.) of mammiferous organ or tissues such as people, dog, cat, bull, horse, pig, monkey, mouse or the prevention or the inhibition of acute rejection or chronic rejection; The host who is caused by bone marrow transplantation is to (GvH) disease of transplant; Allergic disorder (for example specific reaction atopic dermatitis, allergic rhinitis, asthma etc.).
And among the present invention, " prevention " is meant the individuality that does not have morbidity for disease or disease or symptom, administration The compounds of this invention or contain the behavior of its medical composition.And " treatment " is meant the individuality that ill or disease or symptom are taken place, administration The compounds of this invention or contain the behavior of its medical composition.Thereby, to having been found that the individuality of disease or disease or symptom, for the deterioration that prevents symptom etc. or outbreak or the administration behavior of reaccessing are a kind of forms of " treatment ".
When The compounds of this invention is used as medicine; The compounds of this invention can mix with pharmaceutically useful carrier (vehicle, wedding agent, disintegrating agent, correctives, deodorizing agent, emulsifying agent, thinner, dissolving auxiliary etc.), obtains medical composition or with preparation (oral preparation, injection etc.) the oral or non-oral administration of form.Medical composition can be processed preparation through usual method.
Non-oral in this specification sheets is meant and contains subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, topical application or topical (percutaneous drug delivery, administration through eye, through lung, respiratory system administration, nose administration or per rectum administration etc.) etc.
Can with the amount of the The compounds of this invention of carrier combinations can be according to the individuality that will treat and the suitable change of specific administration form.The specific consumption of particular patient according to comprise receive in age, body weight, overall health, sex, diet, administration time, medication, excretion rate and the treatment specified disease about various factors confirm.
The dosage of The compounds of this invention considers perhaps that according to the symptom degree that age, body weight, general state of health, sex, diet, administration time, medication, drainage rate, patient treat at this moment other key elements decide.The compounds of this invention can be to not safe handling of palmic rate with influencing; The dosage of every day is different according to the kind of patient's state or body weight, compound, administration route etc.; For example non-oral administration such as subcutaneous, intravenously, intramuscular, through Leatherwear, through eyes, through lung, respiratory system, through nose or internal rectum; With the amount administration of about 0.01～50mg/ people/day, and oral administration can be with the amount administration of about 0.01～150mg/ people/day.
[embodiment]
In order to illustrate in greater detail the present invention, enumerate embodiment below, but the present invention does not receive any restriction of these embodiment.
Reference example 1
(2,2-dimethyl--5-formyl radical-1,3-diox-5-yl) carboxylamine tertiary butyl ester
(1-1) synthetic (the reference example compound 1-1) of (2,2-dimethyl--5-methylol-1,3-diox-5-yl) carboxylamine tertiary butyl ester
At N, dissolving three (methylol) aminomethane hydrochloride (2g) adds 2 in the dinethylformamide (50ml), and 2-Propanal dimethyl acetal (7.8ml), tosic acid 1 hydrate (229mg) at room temperature stirred 15 hours.In this mixing solutions, add triethylamine (9.5ml) and methyl alcohol (20ml), di-tert-butyl dicarbonic acid ester (4.17g), at room temperature stirred 12 hours.In reaction solution, add entry, behind ethyl acetate extraction, in water, saturated aqueous common salt, clean, use anhydrous magnesium sulfate drying, solvent is removed in underpressure distillation, obtains the title product (3.11g) of colorless solid.
1H-NMR(CDCl 3)δ(ppm)：1.44(3H、s)、1.46(12H、s)、3.73(2H、d、J＝6.4Hz)、3.80(2H、d、J＝11.6Hz)、3.84(2H、d、J＝11.6Hz)、4.20(1H、brs)、5.32(1H、brs)。
(1-2) synthetic (the reference example compound 1-2) of (2,2-dimethyl--5-formyl radical-1,3-diox-5-yl) carboxylamine tertiary butyl ester
The compound (2.96g) of dissolving reference example compound 1-1 adds triethylamine (11ml), sulphur trioxide pyridine coordination compound (5.4g) in DMSO 99.8MIN. (50ml), at room temperature stirs 2 hours.In reaction solution, add entry, behind ethyl acetate extraction, in water, saturated aqueous common salt, clean, use anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated.Residue cleans with diethyl ether, obtains the title product (2.4g) of colourless powder.
1H-NMR(CDCl 3)δ(ppm)：1.46(15H、s)、3.96(2H、d、J＝11.7Hz)、4.07(2H、d、J＝11.7Hz)、5.54(1H、brs)、9.64(1H、s)。
Reference example 2
(4-benzyloxy-3-trifluoromethyl benzyl) triphenyl phosphonium muriate
(2-1) synthetic (the reference example compound 2-1) of 4-fluoro-3-trifluoromethyl TRIMETHOXY BENZOIC ACID (FOR MANUFACTURING OF T.M. benzyl ester
At N, dissolving 4-fluoro-3-trifluoromethyl TRIMETHOXY BENZOIC ACID (FOR MANUFACTURING OF T.M. (1 in the dinethylformamide (400ml)
00g), ice-cold salt of wormwood (199g) and the cylite (84.0g) of adding down, ice-cold stirring down 20 minutes was at room temperature stirred 2 hours again.In reaction solution, add entry, behind ethyl acetate extraction, in water, saturated aqueous common salt, clean, use anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated, and obtains the title product (144g) of faint yellow oily thing.
1H-NMR(CDCl 3)δ(ppm)：5.38(2H、s)、7.27(1H、t、J＝9.3Hz)、7.35-7.46(5H、m)、8.27(1H、m)、8.35(1H、d?d、J＝6.8、1.8Hz)。
(2-2) synthetic (the reference example compound 2-2) of 4-benzyloxy-3-trifluoromethyl TRIMETHOXY BENZOIC ACID (FOR MANUFACTURING OF T.M. benzyl ester
At N, dissolving benzyl ethyl alcohol (52.0g) in the dinethylformamide (300ml), the ice-cold sodium hydride (60%, 20.2g) that adds down ice-coldly stirred 50 minutes down.The N that adds reference example compound 2-1 (144g), dinethylformamide (400ml) solution, ice-cold stirring down 2 hours.In water, add reaction solution, behind ethyl acetate extraction, in water, saturated aqueous common salt, clean, use anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated, and obtains the title product (198g is with the mixture of the MO that contains in the sodium hydride) of faint yellow solid.
1H-NMR(CDCl 3)δ(ppm)：5.26(2H、s)、5.35(2H、s)、7.06(1H、d、J＝8.8Hz)、7.31-7.45(10H、m)、8.18(1H、dd、J＝8.8、2.0Hz)、8.32(1H、d、J＝2.0Hz)。
(2-3) synthetic (the reference example compound 2-3) of 4-benzyloxy-3-trifluoromethyl benzyl alcohol
The compound (198g) that in THF (1000ml), obtains among the dissolving reference example compound 2-2 adds lithium borohydride (15.7g), reflux 3 hours.Once after the cooling, add lithium borohydride (4.0g), reheat refluxed 3 hours.It is ice-cold to have made reaction solution, adds entry (500ml) stopped reaction.In water, add reaction mixture, neutralize with concentrated hydrochloric acid.Behind this mixture of ethyl acetate extraction, in water, saturated aqueous common salt, clean, use anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated.With the mixture that obtains use vacuum pump under reduced pressure, 135 ℃ of heating down, remove impure mineral oil and benzyl alcohol.The residue that obtains crystallization in hexane obtains the title product (99.2g) of white powder.
1H-NMR(CDCl 3)δ(ppm)：1.62(1H、t、J＝5.7Hz)、4.66(2H、d、J＝5.7Hz)、5.20(2H、s)、7.02(1H、d、J＝8.5Hz)、7.30-7.33(1H、m)、7.38(2H、t、J＝7.4Hz)、7.44(2H、d、J＝7.4Hz)、7.46(1H、dd、J＝8.5、2.0Hz)、7.61(1H、d、J＝2.0Hz)。
(2-4) synthetic (the reference example compound 2-4) of 4-benzyloxy-3-trifluoromethyl benzyl chloride thing
The compound (99.2g) that in methylene dichloride (900ml), obtains among the dissolving reference example compound 2-3, ice-cold triphenylphosphine (102g) and the N-chlorosuccinimide (49.3g) of adding down directly stirred 40 minutes down ice-cold, at room temperature stirred 1 hour again.Cleaning reaction liquid is used anhydrous magnesium sulfate drying in water, saturated aqueous common salt, and decompression is heated up in a steamer and desolvated.Add ether (500ml), the residue of removing the triphenylphosphine oxidation thing of separating out at first is with silica gel column chromatography (hexane: vinyl acetic monomer=99: 1～4: 1) make with extra care, obtain the title product (99.5g) of colorless oil.
1H-NMR(CDCl 3)δ(ppm)：4.56(2H、s)、5.20(2H、s)、7.01(1H、d、J＝8.6Hz)、7.31-7.34(1H、m)、7.39(2H、t、J＝7.4Hz)、7.43(2H、d、J＝7.4Hz)、7.48(1H、dd、J＝8.6、2.0Hz)、7.62(1H、d、J＝2.0Hz)。
(2-5) (4-benzyloxy-3-trifluoromethyl benzyl) triphenyl phosphonium muriate (reference example compound 2-5)
The compound (99.0g) that in toluene (450ml), obtains among the dissolving reference example compound 2-4 adds triphenylphosphine (90.7g), refluxes 8 hours.Crystallization in the cooling back leaching reaction solution is cleaned with ether, obtains the purpose compound (132g) of white powder.Behind the concentrated mother liquor, add toluene (200ml),, obtain purpose compound (31.0g) through carrying out aforesaid operations.Handle mother liquor more equally, obtain purpose compound (12.3g).Total output is 176g.
MS(ESI)m/z：527[M +]
1H-NMR(DMSO-d 6)δ(ppm)：5.17(2H、d、J＝15.1Hz)、5.23(2H、s)、7.02-7.04(1H、m)、7.26-7.30(2H、m)、7.31-7.37(1H、m)、7.38-7.42(4H、m)、7.65-7.70(6H、m)、7.72-7.78(6H、m)、7.90-7.94(3H、m)。
Reference example 3
5-bromo-2-oxygen in heptan base benzonitrile
(3-1) synthetic (the reference example compound 3-1) of 5-bromo-2-oxygen in heptan base benzonitrile
At N, dissolving 1-enanthol (1.55g) at room temperature adds sodium hydride (0.321g) in the dinethylformamide (24ml).Stir after 1 hour, add 5-bromo-2-fluoro benzonitrile (2.43g), restir 50 minutes.In water, add reaction solution, use ethyl acetate extraction, in water, saturated aqueous common salt, clean, use anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated.For raw material 5-bromo-2-fluoro benzonitrile is disappeared, again after the reaction under the same conditions, with silica gel column chromatography (hexane: vinyl acetic monomer=50: 1～5: 1) make with extra care, obtain the title product (3.10g) of colorless oil.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.4Hz)、1.24-1.35(6H、m)、1.48(2H、quint、J＝7.2Hz)、1.84(2H、quint、J＝6.4Hz)、4.04(2H、t、J＝6.4Hz)、6.84(1H、d、J＝8.8Hz)、7.59(1H、dd、J＝8.8、2.4Hz)、7.65(1H、d、J＝2.4Hz)。
Embodiment 1
2-amino-2-[2-(4-oxygen in heptan base-3-trifluoromethyl) ethyl] propane-1, the 3-diol hydrochloride
(1-1) synthetic (the compound 1-1) of { 2,2-dimethyl--5-[2-(4-hydroxyl-3-trifluoromethyl) ethyl]-1,3-diox-5-yl } carboxylamine tertiary butyl ester
Dissolving reference example compound 2-5 (70.3g) adds tert.-butoxy potassium (13.0g) in THF (500ml), stirs 1 hour.Behind THF (100ml) solution of the compound (15.0g) of this mixed solution and dripping reference example 1, ice-coldly stirred 2 hours down under the ice-cold condition.In reaction solution, add entry, behind ethyl acetate extraction, in water, saturated aqueous common salt, clean, use anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated.Residue is with silica gel column chromatography (hexane: vinyl acetic monomer=3: 1) make with extra care, obtain the faint yellow oily thing of 31.0g.The geometrical isomer of the compound that obtains in addition, is than being (E: Z=1: 6).
This faint yellow oily thing of dissolving adds 10% year palladium gac (3.00g) in vinyl acetic monomer (200ml), is stirring 7 hours under the atmosphere of hydrogen gas, under the room temperature.After in the nitrogen replacement reaction vessel, filtering solution, concentrated filtrate.Residue cleans with Di Iso Propyl Ether, obtains the title product (22.3g) of colourless powder.
1H-NMR(CDCl 3)δ(ppm)：1.43(3H、s)、1.44(3H、s)、1.47(9H、s)、1.91-1.98(2H、m)、2.50-2.56(2H、m)、3.69(2H、d、J＝11.6Hz)、3.89(2H、d、J＝11.6Hz)、5.02(1H、brs)、5.52(1H、brs)、6.86(1H、d、J＝8.2Hz)、7.22(1H、dd、J＝8.2、1.7Hz)、7.29(1H、d、J＝1.7Hz)。
(1-2) synthetic (the compound 1-2) of { 2,2-dimethyl--5-[2-(4-oxygen in heptan base-3-trifluoromethyl) ethyl]-1,3-diox-5-yl } carboxylamine tertiary butyl ester
At N, dissolved compound 1-1 (510mg) in the dinethylformamide (10ml) adds salt of wormwood (506mg), bromo heptane (0.235ml), stirs 2 hours down at 80 ℃.In reaction solution, add entry, behind ethyl acetate extraction, in water, saturated aqueous common salt, clean, use anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated, and obtains the title product (640mg) of colorless oil.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.8Hz)、1.30-1.37(6H、m)、1.42-1.50(2H、m)、1.42(3H、s)、1.44(3H、s)、1.47(9H、s)、1.76-1.82(2H、m)、1.91-1.98(2H、m)、2.50-2.57(2H、m)、3.69(2H、d、J＝11.6Hz)、3.89(2H、d、J＝11.6Hz)、4.00(2H、t、J＝6.4Hz)、4.98(1H、brs)、6.88(1H、d、J＝8.5Hz)、7.26-7.29(1H、m)、7.35(1H、d、J＝1.5Hz)。
(1-3) 2-amino-2-[2-(4-oxygen in heptan base-3-trifluoromethyl) ethyl] propane-1, synthetic (the compound 1-3) of 3-diol hydrochloride
Dissolved compound 1-2 (640mg) in ethanol (15ml) adds concentrated hydrochloric acid (3ml), stirs 2 hours down at 80 ℃.Concentration of reaction solution, residue cleans with diethyl ether, obtains the title product (492mg) of white powder.
MS(ESI)m/z：378[M+H]
1H-NMR(DMSO-d 6)δ(ppm)：0.86(3H、t、J＝6.8Hz)、1.24-1.39(6H、m)、1.39-1.46(2H、m)、1.68-1.78(4H、m)、2.55-2.62(2H、m)、3.51(4H、d、J＝5.1Hz)、4.06(2H、t、J＝6.2Hz)、5.38(2H、t、J＝5.1Hz)、7.18(1H、d、J＝8.4Hz)、7.42-7.45(2H、m)、7.76(3H、brs)。
Embodiment 2
2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-(phosphinylidyne oxygen ylmethyl) butanols
(2-1) synthetic (the compound 2-1) of [1, two (methylol)-3-(4-oxygen in the heptan base-3-trifluoromethyl) propyl group of 1-] carboxylamine benzyl ester
With compound 1-3 (290mg), vinyl acetic monomer (5ml), saturated sodium bicarbonate aqueous solution (5ml), benzyloxycarbonylchloride base (0.129ml) unevenly former state at room temperature stirred 5 hours.The separating acetic acid methacrylate layer is used the ethyl acetate extraction water layer.Isolating vinyl acetic monomer layer merges with the vinyl acetic monomer layer that extraction obtains, and cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.With the refining (hexane: vinyl acetic monomer=1: 3), obtain the title product (230mg) of colorless oil of silica gel column chromatography.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.8Hz)、1.26-1.39(6H、m)、1.41-1.51(2H、m)、1.75-1.83(2H、m)、1.84-1.91(2H、m)、2.45-2.60(2H、m)、3.03(2H、brs)、3.66-3.71(2H、m)、3.88-3.93(2H、m)、3.99(2H、t、J＝6.3Hz)、5.09(2H、s)、5.31(1H、brs)、6.87(1H、d、J＝8.5Hz)、7.22-7.26(2H、m)、7.31-7.35(5H、m)。
(2-2) synthetic (the compound 2-2) of [1-(dibenzyl) phosphinylidyne oxygen ylmethyl-1-methylol-3-(4-oxygen in heptan base-3-trifluoromethyl) propyl group] carboxylamine benzyl ester
In the mixed solvent of toluene (4ml), methylene dichloride (4ml), PFH (4ml), add compound 2-1 (230mg), tetra-sodium tetrabenzyl ester (485mg), silver suboxide (208m
G), iodate four n-hexyl ammoniums (433mg), at room temperature stirred 15 hours.The elimination insolubles, decompression is heated up in a steamer and desolvated, and is refining with separating HPLC, obtains the title product (210mg) of colorless oil.
MS(ESI)m/z：772[M+H]
1H-NMR(CD 3OD)δ(ppm)：0.91(3H、t、J＝6.4Hz)、1.29-1.44(6H、m)、1.45-1.53(2H、m)、1.74-1.84(3H、m)、1.85-2.02(1H、m)、2.49-2.59(2H、m)、3.59(1H、d、J＝11.2Hz)、3.69(1H、d、J＝11.2Hz)、4.02(2H、t、J＝6.2Hz)、4.15-4.20(1H、m)、4.26-4.31(1H、m)、4.99-5.03(6H、m)、6.98(1H、d、J＝8.5Hz)、7.22-7.34(17H、m)。
(2-3) synthetic (the compound 2-3) of 2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-(phosphinylidyne oxygen ylmethyl) butanols
Dissolved compound 2-2 (210mg) in methyl alcohol (10ml) adds 10% year palladium gac (100mg), uses the hydrogen exchange reaction vessel.After at room temperature stirring 4 hours, nitrogen replacement reaction vessel, filtering reacting liquid.Concentrated filtrate obtains the title product (33.0mg) of white powder.
MS(ESI)m/z：458[M+H]
1H-NMR(CD 3OD)δ(ppm)：0.91(3H、t、J＝6.4Hz)、1.29-1.44(6H、m)、1.45-1.53(2H、m)、1.74-1.82(2H、m)、1.90-1.99(2H、m)、2.60-2.75(2H、m)、3.70(2H、brs)、3.93-3.99(2H、m)、4.04(2H、t、J＝6.2Hz)、7.07(1H、d、J＝8.3Hz)、7.42-7.46(2H、m)。
Embodiment 3
(S)-2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-(phosphinylidyne oxygen ylmethyl) butanols
(3-1) synthetic (the compound 3-1) of N-[1, two (methylol)-3-(4-oxygen in the heptan base-3-trifluoromethyl) propyl group of 1-] ethanamide
In the mixture of compound 1-1 (3.00g), chloroform (300ml), saturated sodium bicarbonate aqueous solution (300ml), whenever added acetic anhydride (1.03ml) while stirring at a distance from 10 minutes, add 8 times.Add at last after the acetic anhydride, stir after 1 and a half hours, separate organic layer, clean with saturated aqueous common salt, use anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated, and obtains the title product (2.96g) of white solid.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.7Hz)、1.30-1.38(6H、m)、1.46(2H、quint、J＝7.3Hz)、1.80(2H、quint、J＝6.9Hz)、1.91-1.96(2H、m)、2.02(3H、s)、2.59-2.63(2H、m)、3.59(2H、brs)、3.63(2H、d、J＝11.8Hz)、3.85(2H、d、J＝10.4Hz)、4.00(2H、t、J＝6.5Hz)、5.92(1H、brs)、6.90(1H、d、J＝8.6Hz)、7.29(1H、dd、J＝2.1、8.6Hz)、7.36(1H、d、J＝2.1Hz)。
(3-2) synthetic (the compound 3-2) of [2-ethanamide-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-methylol] butylacetic acid ester
In methylene dichloride (70ml) solution of compound 3-1 (2.96g), ice-cold pyridine (0.742ml) and the acetic anhydride (0.734ml) of adding down, ice-cold stirring down 7 hours.Add pyridine (0.371ml) and acetic anhydride (0.367ml), ice-cold stirring down 1 hour was at room temperature stirred 14 hours again.Behind methylene dichloride (200ml) dilute reaction solution, clean with 0.1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, saturated aqueous common salt successively, use anhydrous magnesium sulfate drying.Heat up in a steamer through decompression and to desolvate, the residue that obtains is refining with silica gel chromatography, obtains the title product (1.55g) of colorless oil.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.7Hz)、1.28-1.38(6H、m)、1.46(2H、quint、J＝7.3Hz)、1.79(2H、quint、J＝7.0Hz)、1.84-1.92(1H、m)、2.01(3H、s)、2.13(3H、s)、2.13-2.22(1H、m)、2.53(1H、dt、J＝5.1、13.1Hz)、2.66(1H、dt、J＝4.9、13.2Hz)、3.72-3.75(2H、m)、4.00(2H、t、J＝6.4Hz)、4.16(1H、d、J＝11.5Hz)、4.38(1H、d、J＝11.5Hz)、4.40(1H、t、J＝6.8Hz)、5.82(1H、brs)、6.90(1H、d、J＝8.6Hz)、7.28(1H、dd、J＝1.7、8.6Hz)、7.35(1H、d、J＝1.7Hz)。
(3-3) synthetic (the compound 3-3) of 2-ethanamide-2-two (tertiary butyl) phosphinylidyne oxygen ylmethyl-4-(4-oxygen in heptan base-3-trifluoromethyl) butylacetic acid ester
In the solution of the methylene dichloride (50ml) of compound 3-2 (1.55g), 1H-tetrazolium (0.282g) and acetonitrile (50ml), the ice-cold di-t-butyl diisopropylphosphoramidite (1.27ml) that adds down ice-coldly stirred 1.5 hours down.Add 1H-tetrazolium (0.282g) and di-t-butyl diisopropylphosphoramidite (1.27ml), restir 2 hours.In reaction solution ice-cold add down between-chlorine perbenzoic acid (25% hydrate, 0.994g), stirs after 20 minutes, again between the adding-chlorine perbenzoic acid (25% hydrate, 0.994g), stirred 10 minutes.Behind methylene dichloride (100ml) dilute reaction solution, clean with saturated sodium bicarbonate aqueous solution, saturated aqueous common salt successively, use anhydrous magnesium sulfate drying.The residue that heating up in a steamer desolvates obtains that reduces pressure is refining with silica gel chromatography, obtains the title product (1.71g) of colorless oil.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.8Hz)、1.30-1.38(6H、m)、1.42-1.50(2H，m)、1.50(9H、s)、1.51(9H、s)、1.79(2H、quint、J＝7.0Hz)、1.98(3H、s)、2.02-2.10(1H、m)、2.07(3H、s)、2.32-2.40(1H、m)、2.50-2.65(2H、m)、4.00(2H、t、J＝6.3Hz)、4.09(2H、d、J＝8.4Hz)、4.37(1H、d、J＝11.1Hz)、4.47(1H、t、J＝11.1Hz)、6.67(1H、brs)、6.88(1H、d、J＝8.6Hz)、7.28(1H、dd、J＝1.5、8.6Hz)、7.35(1H、d、J＝1.5Hz)。
(3-4) (S)-2-ethanamide-2-two (tertiary butyl) phosphinylidyne oxygen ylmethyl-4-(4-oxygen in heptan base-3-trifluoromethyl) butylacetic acid ester (compound 3-4-1) and (R)-2-ethanamide-2-two (tertiary butyl) phosphinylidyne oxygen ylmethyl-4-(4-oxygen in heptan base-3-trifluoromethyl) butylacetic acid ester (compound 3-4-2) is synthetic
Use the HPLC of CHIRALPAK (registered trademark) AD-H (hexane/ethanol/Diisopropylamine) to come separating compound 3-3 (1.47g), obtain two enantiotropies of colorless oil.Hold-time, short first peak was S body (0.55g, compound 3-4-1), and the hold-time, the second long peak was R body (0.65g, compound 3-4-2).
(3-5) synthetic (the compound 3-5) of (S)-2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-(phosphinylidyne oxygen ylmethyl) butanols
With ethanol (15ml) and hydrochloric acid (3ml) dissolved compound 3-4-1 (0.55g), stirred 3 hours down at 50 ℃.In water (150ml), inject reaction solution, former state was placed 7 hours.The solid that leaching is separated out, water cleans after drying, obtains the title product (0.33g) of white powder.
MS(ESI)m/z：458[M+H]
1H-NMR(CD 3OD)δ(ppm)：0.91(3H、t、J＝6.8Hz)、1.29-1.41(6H、m)、1.45-1.53(2H、m)、1.74-1.81(2H、m)、1.89-1.99(2H、m)、2.60-2.75(2H、m)、3.70(2H、brs)、3.94-4.02(2H、m)、4.04(2H、t、J＝6.2Hz)、7.07(1H、d、J＝8.4Hz)、7.42-7.46(2H、m)。
Embodiment 4
(4-1) synthetic (the compound 4-1) of (R)-2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-(phosphinylidyne oxygen ylmethyl) butanols
With ethanol (15ml) and hydrochloric acid (3ml) dissolved compound 3-4-2 (0.65g), stirred 2.5 hours down at 50 ℃.In water (150ml), inject reaction solution, former state was placed 4 hours.The solid that leaching is separated out, after washing, drying obtains the title product (0.35g) of white powder.
MS(ESI)m/z：458[M+H]
1H-NMR(CD 3OD)δ(ppm)：0.91(3H、t、J＝6.8Hz)、1.29-1.41(6H、m)、1.45-1.53(2H、m)、1.74-1.81(2H、m)、1.90-2.01(2H、m)、2.61-2.74(2H、m)、3.69(1H、d、J＝12.0Hz)、3.70(1H、d、J＝12.0Hz)、3.93-4.02(2H、m)、4.04(2H、t、J＝6.2Hz)、7.07(1H、d、J＝8.4Hz)、7.42-7.46(2H、m)。
Embodiment 5
2-amino-2-[2-(3-cyanic acid-4-oxygen in heptan base phenyl) ethyl] propane-1, the 3-diol hydrochloride
(5-1) synthetic (the compound 5-1) of { 2,2-dimethyl--5-[2-(3-cyanic acid-4-oxygen in heptan base phenyl) ethyl]-1,3-diox-5-yl } carboxylamine tertiary butyl ester
Under 70 ℃; Add reference example compound 3-1 (836mg) in the mixed solvent of acetonitrile (15ml), THF (2ml), by known method (for example tetrahedron (tetrahedron) the 57th volume (calendar year 2001) 6531-6538 page or leaf) synthetic (2; 2-dimethyl--5-ethynyl-1; 3-diox-5-yl) carboxylamine tertiary butyl ester (482mg), 2-dicyclohexyl phosphino--2 '; 4 ', 6 '-tri isopropyl biphenyl base (54mg), two (acetonitrile) palladium (II) dichloride (10mg), cesium carbonate (919mg) stirred 4 hours.In reaction solution, add entry, behind ethyl acetate extraction, clean with saturated aqueous common salt, use anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated.Residue is with silica gel column chromatography (hexane: vinyl acetic monomer=4: 1) make with extra care, obtain brown oil (493mg) [2,2-dimethyl--5-(3-cyanic acid-4-oxygen in heptan base phenyl) ethynyl-1,3-diox-5-yl] carboxylamine tertiary butyl ester.This midbody adds lindlar catalyst (80mg) with vinyl acetic monomer (5ml) dissolving, under atmosphere of hydrogen gas, stirs an evening.Behind the filtering reacting liquid, concentrate the residue that obtains and dissolve with ethanol (4ml), (quadrol is poisoned, and 40mg), is stirring 2.5 hours under the atmosphere of hydrogen gas, under the room temperature to add 10% year palladium gac.Filtering solution, concentrated filtrate obtains title product (182mg).
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝7.2Hz)、1.26-1.31(6H、m)、1.35-1.37(2H、m)、1.43(3H、s)、1.44(3H、s)、1.47(9H、s)、1.78-1.86(2H、m)、1.91-1.96(2H、m)、2.49-2.53(2H、m)、3.68(2H、d、J＝11.6Hz)、3.87(2H、d、J＝11.6Hz)、4.02(2H、t、J＝6.4Hz)、4.99(1H、brs)、6.85(1H、d、J＝8.4Hz)、7.32(1H、dd、J＝8.4、1.6Hz)、7.33(1H、m)。
(5-2) 2-amino-2-[2-(3-cyanic acid-4-oxygen in heptan base phenyl) ethyl] propane-1, synthetic (the compound 5-2) of 3-diol hydrochloride
Dissolved compound 5-1 (255mg) in ethanol (2ml) adds tosic acid (19mg), at room temperature stirs 4 hours.In reaction solution, add saturated sodium bicarbonate water, behind ethyl acetate extraction, clean with saturated aqueous common salt, use anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated.Residue is with silica gel column chromatography (hexane: vinyl acetic monomer=4: 1) make with extra care, obtain oily matter.In this oily matter, add and contain hydrogenchloride De diox (4mol/l), at room temperature stirred 3 hours.The leaching precipitate, drying obtains the title product (45mg) of white powder.
MS(ESI)m/z：335[M+H]
1H-NMR(DMSO-d 6)δ(ppm)：0.86(3H、t、J＝6.8Hz)、1.26-1.37(6H、m)、1.38-1.44(2H、m)、1.69-1.77(4H、m)、2.55-2.59(2H、m)、3.50(4H、d、J＝4.4Hz)、4.09(2H、t、J＝6.4Hz)、5.38(2H、t、J＝4.4Hz)、7.18(1H、d、J＝8.8Hz)、7.49(1H、dd、J＝8.8、2.0Hz)、7.55(1H、d、J＝2.0Hz)、7.82(3H、brs)。
Embodiment 6
2-amino-4-(3-cyanic acid-4-oxygen in heptan base phenyl)-2-(phosphinylidyne oxygen ylmethyl) butanols
(6-1) synthetic (the compound 6-1) of [3-(3-cyanic acid-4-oxygen in heptan base phenyl)-1-(dibenzyl) phosphinylidyne oxygen ylmethyl-1-methylol propyl group] carboxylamine tertiary butyl ester
Dissolved compound 5-1 (340mg) in ethanol (3ml) adds tosic acid monohydrate (0.025g), at room temperature stirs 6 hours.In reaction solution, add entry,, behind ethyl acetate extraction, clean, use SODIUM SULPHATE ANHYDROUS 99PCT, heat up in a steamer and desolvate, obtain the compound of removing acetonide (300mg) as colorless oil with saturated aqueous common salt with saturated sodium bicarbonate water neutralization.Get the 205mg in this colorless oil, be dissolved in the mixed solvent of methylene dichloride (2ml) and toluene (2ml), add PFH (2ml), silver suboxide (219mg), tetra-sodium tetrabenzyl ester (508mg), at room temperature stir.Add iodate four n-hexyl ammoniums (454mg), restir 5 hours after 5 minutes.Behind the elimination insolubles, heat up in a steamer and desolvate, with to separate HPLC refining, obtain the title product (81.0mg) of colorless oil with silica gel chromatography.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.4Hz)、1.31-1.36(6H、m)、1.43(9H、s)、1.64-1.71(2H、m)、1.79-1.86(2H、m)、1.99-2.06(2H、m)、2.39-2.49(2H、m)、3.50-3.55(2H、m)、4.02(2H、t、J＝6.4Hz)、4.10(1H、d、J＝7.2Hz)、4.13(1H、d、J＝7.2Hz)、5.00(1H、s)、5.03-5.09(4H、m)、6.82(1H、d、J＝8.4Hz)、7.26-7.27(2H、m)、7.32-7.34(10H、m)。
(6-2) synthetic (the compound 6-2) of 2-amino-4-(3-cyanic acid-4-oxygen in heptan base phenyl)-2-(phosphinylidyne oxygen ylmethyl) butanols
Dissolved compound 6-1 (81.0mg) in acetonitrile (2ml) adds Soiodin (140mg), chloro trimethyl silane (0.12ml), at room temperature stirs 4 and a half hours.Add water and vinyl acetic monomer, beginning UW, the solid that leaching generates.Water and vinyl acetic monomer clean this solid, and drying obtains the title product (35.0mg) of pale yellow powder.
MS(ESI)m/z：415[M+H]
1H-NMR(CD 3OD)δ(ppm)：0.86(3H、t、J＝6.8Hz)、1.32-1.39(6H、m)、1.47-1.53(2H、m)、1.79-1.83(2H、m)、1.89-1.95(2H、m)、2.63-2.67(2H、m)、3.68(2H、d、J＝2.0Hz)、3.96(2H、t、J＝6.4Hz)、4.10(2H、t、J＝6.4Hz)、7.08(1H、d、J＝9.2Hz)、7.49-7.51(2H、m)。
Embodiment 7
2-amino-2-[2-(3-cyanic acid-4-octyloxyphenyl) ethyl] propane-1, the 3-diol hydrochloride
(7-1) synthetic (the compound 7-1) of 5-bromo-2-octyloxy benzonitrile
At N, dissolving octanol (0.834g) in the dinethylformamide (10ml) adds sodium hydride (60%, 0.256g).Stir after 30 minutes, add 5-bromo-2-fluoro benzonitrile (0.640g), stirred 1 hour down at 40-50 ℃ again.In water, add reaction solution, use ethyl acetate extraction, in water, saturated aqueous common salt, clean, use anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated.Make with extra care with silica gel column chromatography, obtain the title product (1.042g) of colorless oil.
1H-NMR(CDCl 3)δ(ppm)：0.88(3H、t、J＝6.8Hz)、1.24-1.37(8H、m)、1.44-1.51(2H、m)、1.80-1.87(2H、m)、4.04(2H、t、J＝6.4Hz)、6.83(1H、d、J＝8.8Hz)、7.59(1H、dd、J＝8.8、2.4Hz)、7.64(1H、d、J＝2.4Hz)。
(7-2) synthetic (the compound 7-2) of { 2,2-dimethyl--5-[2-(3-cyanic acid-4-octyloxyphenyl) ethyl]-1,3-diox-5-yl } carboxylamine tertiary butyl ester
In acetonitrile (10ml), add compound 7-1 (0.636g), (2; 2-dimethyl--5-ethynyl-1; 3-diox-5-yl) carboxylamine tertiary butyl ester (0.571g), 2-dicyclohexyl phosphino--2 '; 4 ', 6 '-tri isopropyl biphenyl base (0.045g), two (acetonitrile) palladium (I I) dichloride (0.008g), cesium carbonate (0.668g) stirred 2 hours down at 70-80 ℃.In reaction solution, add entry, behind ethyl acetate extraction, clean with saturated aqueous common salt, use anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated.Residue is refining with silica gel column chromatography, obtains [2,2-dimethyl--5-(3-cyanic acid-4-octyloxyphenyl ethynyl)-1,3-diox-5-yl] the carboxylamine tertiary butyl ester as brown oil.This oily matter is with vinyl acetic monomer (6ml) dissolving, adds 10% year palladium gac (contain 50% the moisture of having an appointment, 0.080g), stirring under the atmosphere of hydrogen gas, under the room temperature 3 and a half hours.Filtering solution, concentrated filtrate obtains the title product (0.610g) of pale yellow powder.
1H-NMR(CDCl 3)δ(ppm)：0.88(3H、t、J＝6.8Hz)、1.27-1.34(8H、m)、1.41-1.43(2H、m)、1.42(3H、s)、1.43(3H、s)、1.46(9H、s)、1.78-1.85(2H、m)、1.92-1.96(2H、m)、2.49-2.53(2H、m)、3.67(2H、d、J＝11.6Hz)、3.86(2H、d、J＝11.6Hz)、4.02(2H、t、J＝6.4Hz)、4.97(1H、s)、6.84(1H、d、J＝8.8Hz)、7.33(1H、dd、J＝8.8、2.0Hz)、7.34(1H、d、J＝2.0Hz)。
(7-3) 2-amino-2-[2-(3-cyanic acid-4-octyloxyphenyl) ethyl] propane-1, synthetic (the compound 7-3) of 3-diol hydrochloride
Dissolved compound 7-2 (0.610g) in the mixed solvent of ethanol (5ml) and THF (2ml) adds tosic acid monohydrate (0.043g), at room temperature stirs 3 and a half hours, stirs 2 and a half hours down at 50-60 ℃ again.In reaction solution, add saturated sodium bicarbonate water, behind ethyl acetate extraction, clean with saturated aqueous common salt, use anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated.Residue is refining with silica gel column chromatography, obtains the compound of embodiment (6-2) the acetal deprotection of oily matter.In the oily matter that obtains, add and contain hydrogenchloride De diox (4mol/l, 2ml), at room temperature stirred 8 hours.The leaching precipitate, drying obtains the title product (145mg) of white powder.
MS(ESI)m/z：349[M+H]
1H-NMR(DMSO-d 6)δ(ppm)：0.86(3H、t、J＝6.8Hz)、1.26-1.35(8H、m)、1.40-1.46(2H、m)、1.69-1.76(4H、m)、2.54-2.58(2H、m)、3.49(4H、d、J＝4.4Hz)、4.09(2H、t、J＝6.4Hz)、5.39(2H、brs)、7.18(1H、d、J＝8.8Hz)、7.49(1H、d、J＝8.8Hz)、7.54(1H、s)、7.63(3H、brs)。
Embodiment 8
2-amino-4-(3-cyanic acid-4-octyloxyphenyl)-2-(phosphinylidyne oxygen ylmethyl) butanols
(8-1) synthetic (the compound 8-1) of [3-(3-cyanic acid-4-octyloxyphenyl) 1-(dibenzyl) phosphinylidyne oxygen ylmethyl-1-methylol propyl group] carboxylamine tertiary butyl ester
Dissolved compound 7-2 (208mg) in ethanol (2ml) adds tosic acid monohydrate (73.0mg), at room temperature stirs 6 and a half hours.In reaction solution, add entry,, behind ethyl acetate extraction, clean, use anhydrous sodium sulfate drying, heat up in a steamer and desolvate with saturated aqueous common salt with saturated sodium bicarbonate water neutralization.The residue that obtains dissolves in the mixed solvent of methylene dichloride (2ml) and toluene (2ml), adds PFH (2ml), silver suboxide (197mg), tetra-sodium tetrabenzyl ester (459mg), at room temperature stirs.Add iodate four n-hexyl ammoniums (410mg), restir 17 hours after 5 minutes.Behind the elimination insolubles, heat up in a steamer and desolvate, make with extra care with preparation HPLC, obtain the title product (106mg) of colorless oil with silica gel chromatography.
1H-NMR(CDCl 3)δ(ppm)：0.88(3H、t、J＝6.8Hz)、1.27-1.34(6H、m)、1.43(9H、s)、1.46-1.51(2H、m)、1.78-1.86(2H、m)、1.79-1.86(2H、m)、2.00-2.06(2H、m)、2.39-2.51(2H、m)、3.47-3.56(2H、m)、3.90-3.92(1H、m)、3.97-4.06(4H、m)、4.79(1H、s)、5.03-5.07(4H、m)、6.84(1H、d、J＝8.0Hz)、7.26(1H、d、J＝8.0Hz)、7.34-7.35(11H、m)。
(8-2) synthetic (the compound 8-2) of 2-amino-4-(3-cyanic acid-4-octyloxyphenyl)-2-(phosphinylidyne oxygen ylmethyl) butanols
Dissolved compound 8-1 (104mg) in acetonitrile (2ml) adds Soiodin (110mg), chloro trimethyl silane (80.0mg), at room temperature stirs 3 hours.Add water and vinyl acetic monomer, beginning UW, the solid that leaching generates.This solid water and vinyl acetic monomer are used washed with methanol after cleaning again, and drying obtains the title product (26.0mg) of white powder.
MS(ESI)m/z：429[M+H]
1H-NMR(CD 3OD)δ(ppm)：0.89(3H、t、J＝6.8Hz)、1.31-1.35(8H、m)、1.50-1.52(2H、m)、1.79-1.83(2H、m)、1.89-1.92(2H、m)、2.63-2.67(2H、m)、3.63-3.67(2H、m)、3.95-3.97(2H、m)、4.09(2H、t、J＝6.4Hz)、7.07(1H、d、J＝9.2Hz)、7.49-7.50(2H、m)。
Embodiment 9
2-amino-2-[2-(4-octyloxy-3-trifluoromethyl) ethyl] propane-1, the 3-diol hydrochloride
(9-1) 4 '-methoxyl group-3 '-synthetic (the compound 9-1) of trifluoromethyl acetophenone
4 '-fluoro-3 '-N of trifluoromethyl acetophenone (25.0g), in dinethylformamide (70ml) solution, the ice-cold sodium methoxide (7.21g) that adds down ice-coldly stirred 2 hours down, at room temperature stirred 1 hour again.In water, add reaction solution, behind ethyl acetate extraction, clean organic layer with saturated aqueous common salt, use anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated, and obtains dark brown solid title product (24.3g).
1H-NMR(CDCl 3)δ(ppm)：2.59(3H、s)、3.99(3H、s)、7.06(1H、d、J＝8.7Hz)、8.14(1H、dd、J＝2.1、8.7Hz)、8.19(1H、d、J＝2.1Hz)。
(9-2) 4 '-methoxyl group-3 '-synthetic (the compound 9-2) of trifluoromethyl phenacyl bromide thing
In acetic acid (120ml) solution of compound 9-1 (24.3g), add pyridine tribromide (90%, 39.6g), stirred 1 hour down at 50 ℃.In frozen water, add reaction solution, behind ethyl acetate extraction, organic layer water, 1M aqueous sodium hydroxide solution, saturated ammonium chloride, saturated aqueous common salt successively cleans.This organic layer is used anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated, and obtains dark brown solid title product (34.2g).
1H-NMR(CDCl 3)δ(ppm)：4.01(3H、s)、4.39(2H、s)、7.09(1H、d、J＝8.7Hz)、8.18(1H、dd、J＝2.2、8.7Hz)、8.23(1H、d、J＝1.9Hz)。
(9-3) synthetic (the compound 9-3) of 2-acetamido-2-[2-(4-methoxyl group-3-trifluoromethyl)-2-oxoethyl] ethyl malonate
The N of 2-ethanamide propanedioic acid diethyl ester (20.1g), in dinethylformamide (100ml) solution, the ice-cold sodium hydride (60%, 4.07g) that adds at twice down stirred 30 minutes.The N that in this solution, adds compound 9-2 (33.0g), dinethylformamide (50ml) solution, ice-cold stirring down 2 hours.Reaction solution joins in the frozen water, and behind ethyl acetate extraction, organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains is refining with silica gel chromatography, obtains the title product (31.8g) of dark brown oily matter.
1H-NMR(CDCl 3)δ(ppm)：1.25(6H、t、J＝7.1Hz)、1.97(3H、s)、3.98(3H、s)、4.22(2H、s)、4.27(4H、dq、J＝2.4、7.1Hz)、7.05(1H、d、J＝8.7Hz)、7.09(1H、brs)、8.13(1H、dd、J＝2.2、8.7Hz)、8.20(1H、d、J＝2.0Hz)。
(9-4) synthetic (the compound 9-4) of 2-acetamido-2-[2-(4-methoxyl group-3-trifluoromethyl) ethyl] propanedioic acid diethyl ester
In trifluoracetic acid (230ml) solution of compound 9-3 (31.5g), add triethyl silicane (116ml), stirred 13 hours down at 70 ℃.Reaction solution adds entry after under reduced pressure concentrating, and uses ethyl acetate extraction.Organic layer is used anhydrous magnesium sulfate drying after cleaning with aqueous sodium hydroxide solution, saturated aqueous common salt successively, and decompression is heated up in a steamer and desolvated.The residue that obtains is refining with silica gel chromatography, obtains the mixture yellow oil of motif compound and raw material.In trifluoracetic acid (230ml) solution of this oily matter, add triethyl silicane (116ml), stirred 12 hours down at 70 ℃.Reaction solution adds entry behind concentrating under reduced pressure, use ethyl acetate extraction.Organic layer is used anhydrous magnesium sulfate drying after cleaning with aqueous sodium hydroxide solution, saturated aqueous common salt successively, and decompression is heated up in a steamer and desolvated.Add diethyl ether in the residue that obtains, the solid that leaching is separated out, drying obtains the title product (7.91g) of white powder.Behind the concentrated mother liquor, refining under the decompression with silica gel chromatography, obtain title product (4.29g).Total output is 12.2g.
1H-NMR(CDCl 3)δ(ppm)：1.25(6H、t、J＝7.2Hz)、2.02(3H、s)、2.44-2.48(2H、m)、2.62-2.68(2H、m)、3.87(3H、s)、4.15-4.27(4H、m)、6.78(1H、brs)、6.90(1H、d、J＝8.4Hz)、7.27(1H、dd、J＝2.0、8.4Hz)、7.32(1H、d、J＝2.0Hz)。
(9-5) synthetic (the compound 9-5) of N-[1, two (methylol)-3-(4-methoxyl group-3-trifluoromethyl) propyl group of 1-] ethanamide
In the solution of the ethanol (200ml) of compound 9-4 (12.2g) and water (40ml), add calcium chloride (6.46g), make its dissolving.In this mixed solution, the ice-cold Peng Qinghuana (4.40g) that adds at twice down, ice-cold stirring down 3 hours was at room temperature stirred 20 hours again.The ice-cold 1M hydrochloric acid (300ml) that adds down in reaction solution, decompression is used ethyl acetate extraction after concentrating down.Behind saturated aqueous common salt cleaning organic layer, use anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated, and obtains the title product (9.88g) of white blister.
1H-NMR(CDCl 3)δ(ppm)：1.92-1.96(2H、m)、2.02(3H、s)、2.60-2.64(2H、m)、3.57(2H、brs)、3.64(2H、brd、J＝11.6Hz)、3.85(2H、brd、J＝11.6Hz)、3.87(3H、s)、5.94(1H、brs)、6.92(1H、d、J＝8.5Hz)、7.32(1H、dd、J＝1.9、8.5Hz)、7.37(1H、d、J＝1.9Hz)。
(9-6) synthetic (the compound 9-6) of [1, two (methylol)-3-(4-hydroxyl-3-trifluoromethyl) propyl group of 1-] carboxylamine tertiary butyl ester
In methylene dichloride (90ml) solution of compound 9-5 (9.70g), at-70 ℃ of 1M dichloromethane solutions (116ml) that drip boron tribromide down.In 1 hour, be warmed up to 0 ℃ while stirring, stirred 2 hours down ice-cold again.At the ice-cold methyl alcohol (200ml) that slowly adds down of reaction solution, decompression concentrates down.In ethanol (50ml) solution of the residue that obtains, add concentrated hydrochloric acid (50ml), stirred 1 hour down at 70 ℃.Decompression is concentration of reaction solution down, and at residue that obtains and N, in methyl alcohol (80ml) solution of N-diisopropylethylamine (12.6ml), the ice-cold di-tert-butyl dicarbonic acid ester (6.94g) that adds down ice-coldly stirred 2 hours down, again stirring at room 4 hours.In reaction solution, add saturated sodium bicarbonate aqueous solution (500ml), decompression is used ethyl acetate extraction after concentrating down.Organic layer cleans with saturated sodium bicarbonate aqueous solution, saturated aqueous common salt successively, and behind anhydrous magnesium sulfate drying, decompression is heated up in a steamer and desolvated.The residue that obtains is refining with silica gel chromatography, obtains the title product (2.15g) of colorless oil.
1H-NMR(CDCl 3)δ(ppm)：1.46(9H、s)、1.84-1.89(2H、m)、2.57-2.61(2H、m)、3.26(2H、brs)、3.66(2H、dd、J＝5.9、11.4Hz)、3.87(2H、dd、J＝5.2、11.4Hz)、5.04(1H、brs)、5.58(1H、brs)、6.87(1H、d、J＝8.4Hz)、7.23(1H、dd、J＝1.8、8.4Hz)、7.30(1H、d、J＝1.8Hz)。
(9-7) synthetic (the compound 9-7) of [1, two (methylol)-3-(4-octyloxy-3-trifluoromethyl) propyl group of 1-] carboxylamine tertiary butyl ester
At N, dissolved compound 9-6 (360mg) in the dinethylformamide (10ml) adds salt of wormwood (263mg), 1-bromooctane (0.198ml), stirs 6 hours down at 80 ℃.Add entry in the reaction solution, behind ethyl acetate extraction, in water, saturated aqueous common salt, clean, use anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated, and obtains the title product (490mg) of colorless oil.
1H-NMR(CDCl 3)δ(ppm)：0.88(3H、t、J＝6.8Hz)、1.23-1.40(8H、m)、1.41-1.50(2H、m)、1.47(9H、s)、1.75-1.82(2H、m)、1.83-1.90(2H、m)、2.57-2.62(2H、m)、3.28(2H、brs)、3.63-3.67(2H、m)、3.85-3.90(2H、m)、4.00(2H、t、J＝6.4Hz)、5.02(1H、brs)、6.89(1H、d、J＝8.5Hz)、7.27(1H、dd、J＝8.5、1.9Hz)、7.36(1H、d、J＝1.9Hz)。
(9-8) 2-amino-2-[2-(4-octyloxy-3-trifluoromethyl) ethyl] propane-1, synthetic (the compound 9-8) of 3-diol hydrochloride
Dissolved compound 9-7 (490mg) in methylene dichloride (5ml) adds and contains hydrogenchloride De diox (4mol/l, 5ml), at room temperature stirs 12 hours.Concentration of reaction solution, residue cleans with diethyl ether, obtains the title product (350mg) of white powder.
MS(ESI)m/z：392[M+H]
1H-NMR(CD 3OD)δ(ppm)：0.90(3H、t、J＝6.8Hz)、1.24-1.41(8H、m)、1.47-1.53(2H、m)、1.75-1.81(2H、m)、1.91-1.97(2H、m)、2.63-2.70(2H、m)、3.69(4H、s)、4.05(2H、t、J＝6.2Hz)、7.03(1H、d、J＝8.4Hz)、7.41(1H、d、J＝8.4Hz)、7.44(1H、brs)。
Embodiment 10
2-amino-4-(4-octyloxy-3-trifluoromethyl)-2-(phosphinylidyne oxygen ylmethyl) butanols
(10-1) synthetic (the compound 10-1) of 4-two (tertiary butyl) phosphinylidyne oxygen ylmethyl-2-methyl-4-[2-(4-octyloxy-3-trifluoromethyl) ethyl]-2-oxazoline
At the N of compound 9-8 (270mg), add N in dinethylformamide (7ml) solution, N-diisopropylethylamine (0.340ml), original trimethyl acetate (0.121ml) stirred 5 and a half hours down at 120 ℃.In reaction solution, add entry, behind ethyl acetate extraction, in water, saturated aqueous common salt, clean, use anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated, and obtains the 280mg brown oil.In the solution of the methylene dichloride (5ml) of this brown oil (280mg) and acetonitrile (2ml), add 1H-tetrazolium (88mg), di-t-butyl diethylammonium phosphoramidite (0.377ml), at room temperature stirred 2 hours.Ice-cold reaction soln, between adding-(25% hydrate 335mg), at room temperature stirred 30 minutes the chloro perbenzoic acid.In reaction solution, add saturated sodium bicarbonate aqueous solution, behind chloroform extraction, organic layer is used anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains with silica gel column chromatography (hexane: vinyl acetic monomer=1: 3～have only vinyl acetic monomer) refining, obtain the title product (190mg) of brown oil.
1H-NMR(CDCl 3)δ(ppm)：0.90(3H、t、J＝6.9Hz)、1.28-1.40(8H、m)、1.47-1.52(2H、m)、1.48(9H、s)、1.49(9H、s)、1.70-1.90(4H、m)、2.01(3H、s)、2.51-2.71(2H、m)、3.89-3.92(2H、m)、4.04(2H、t、J＝6.2Hz)、4.17(1H、d、J＝9.0Hz)、4.32(1H、d、J＝9.0Hz)、7.05(1H、d、J＝8.4Hz)、7.36-7.41(2H、m)。
(10-2) synthetic (the compound 10-2) of 2-amino-4-(4-octyloxy-3-trifluoromethyl)-2-(phosphinylidyne oxygen ylmethyl) butanols
Dissolved compound 10-1 (190mg) in ethanol (5ml) adds concentrated hydrochloric acid (1ml), stirs 3 hours down at 50 ℃.The concentrating under reduced pressure solvent adds methyl alcohol (5ml), diethyl ether (5m in the residue
L), propylene oxide (5ml), the powder that leaching is separated out cleans with vinyl acetic monomer and diethyl ether, obtains the title product (137mg) of white solid.
MS(ESI)m/z：472[M+H]
1H-NMR(CD 3OD)δ(ppm)：0.90(3H、t、J＝6.4Hz)、1.25-1.40(8H、m)、1.45-1.53(2H、m)、1.76-1.83(2H、m)、1.93-2.00(2H、m)、2.63-2.74(2H、m)、3.70(2H、brs)、3.96-4.00(2H、m)、4.04(2H、t、J＝6.2Hz)、7.07(1H、d、J＝8.3Hz)、7.42-7.46(2H、m)。
Embodiment 11
2-amino-2-[2-(4-hexyloxy-3-trifluoromethyl) ethyl] propane-1, the 3-diol hydrochloride
(11-1) synthetic (the compound 11-1) of { 2,2-dimethyl--5-[2-(4-hexyloxy-3-trifluoromethyl) ethyl]-1,3-diox-5-yl } carboxylamine tertiary butyl ester
At N, dissolved compound 1-1 (500mg) in the dinethylformamide (10ml) adds salt of wormwood (494mg), 1-bromo hexane (0.201ml), stirs 2 hours down at 80 ℃.Add entry in the reaction solution, behind ethyl acetate extraction, in water, saturated aqueous common salt, clean, use anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated, and obtains the title product (620mg) of colorless oil.
1H-NMR(CDCl 3)δ(ppm)：0.90(3H、t、J＝6.9Hz)、1.30-1.36(4H、m)、1.41-1.50(2H、m)、1.43(3H、s)、1.44(3H、s)、1.47(9H、s)、1.76-1.81(2H、m)、1.91-1.99(2H、m)、2.51-2.56(2H、m)、3.69(2H、d、J＝11.7Hz)、3.89(2H、d、J＝11.7Hz)、4.00(2H、t、J＝6.4Hz)、4.98(1H、brs)、6.88(1H、d、J＝8.5Hz)、7.26-7.28(1H、m)、7.35(1H、d、J＝1.6Hz)。
(11-2) 2-amino-2-[2-(4-hexyloxy-3-trifluoromethyl) ethyl] propane-1, synthetic (the compound 11-2) of 3-diol hydrochloride
Dissolved compound 11-1 (620mg) in ethanol (15ml) adds concentrated hydrochloric acid (2.5ml), stirs 3 hours down at 80 ℃.Concentration of reaction solution, residue cleans with diethyl ether, obtains the title product (465mg) of white powder.
MS(ESI)m/z：364[M+H]
1H-NMR(CD 3OD)δ(ppm)：0.91(3H、t、J＝6.9Hz)、1.32-1.40(4H、m)、1.47-1.53(2H、m)、1.73-1.81(2H、m)、1.90-1.96(2H、m)、2.62-2.68(2H、m)、3.68(4H、d、J＝5.1Hz)、4.04(2H、t、J＝6.2Hz)、7.07(1H、d、J＝8.4Hz)、7.41(1H、dd、J＝8.4、1.9Hz)、7.45(1H、d、J＝1.9Hz)。
Embodiment 12
2-amino-4-(4-hexyloxy-3-trifluoromethyl)-2-(phosphinylidyne oxygen ylmethyl) butanols
(12-1) synthetic (the compound 12-1) of 4-two (tertiary butyl) phosphinylidyne oxygen ylmethyl-4-[2-(4-hexyloxy-3-trifluoromethyl) ethyl]-2-methyl-2-oxazoline
At the N of compound 11-2 (380mg), in dinethylformamide (10ml) solution, add N, N-diisopropylethylamine (0.512ml), original trimethyl acetate (0.180ml) stirred 12 hours down at 120 ℃.Add entry in the reaction solution, behind ethyl acetate extraction, in water, saturated aqueous common salt, clean, use anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated, and obtains the 380mg brown oil.In the solution of the methylene dichloride (5ml) of this brown oil (380mg) and acetonitrile (2ml), add 1H-tetrazolium (133mg), di-t-butyl diethylammonium phosphoramidite (0.569ml), at room temperature stirred 2 hours.Ice-cold reaction soln, between adding-(25% hydrate 504mg), at room temperature stirred 1 hour the chloro perbenzoic acid.In reaction solution, add saturated sodium bicarbonate aqueous solution, behind chloroform extraction, organic layer is used anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains with silica gel column chromatography (hexane: vinyl acetic monomer=1: 4～have only vinyl acetic monomer) refining, obtain the title product (220mg) of yellow oil.
1H-NMR(CDCl 3)δ(ppm)：0.93(3H、t、J＝6.9Hz)、1.30-1.40(4H、m)、1.47-1.52(2H、m)、1.48(9H、s)、1.49(9H、s)、1.74-1.88(4H、m)、2.01(3H、s)、2.51-2.70(2H、m)、3.87-3.92(2H、m)、4.04(2H、t、J＝6.2Hz)、4.18(1H、d、J＝8.9Hz)、4.32(1H、d、J＝8.9Hz)、7.05(1H、d、J＝8.4Hz)、7.37-7.41(2H、m)。
(12-2) synthetic (the compound 12-2) of 2-amino-4-(4-hexyloxy-3-trifluoromethyl)-2-(phosphinylidyne oxygen ylmethyl) butanols
Dissolved compound 12-1 (220mg) in ethanol (5ml) adds concentrated hydrochloric acid (1ml), stirs 3 hours down at 50 ℃.The concentrating under reduced pressure solvent adds methyl alcohol (5ml), diethyl ether (5ml), propylene oxide (5ml) in residue, the powder that leaching is separated out cleans with vinyl acetic monomer and diethyl ether, obtains the title product (118mg) of white solid.
MS(ESI)m/z：444[M+H]
1H-NMR(CD 3OD)δ(ppm)：0.91(3H、t、J＝6.9Hz)、1.31-1.40(4H、m)、1.45-1.54(2H、m)、1.74-1.82(2H、m)、1.92-1.98(2H、m)、2.60-2.75(2H、m)、3.70(2H、brs)、3.93-3.99(2H、m)、4.04(2H、t、J＝6.2Hz)、7.07(1H、d、J＝8.2Hz)、7.42-7.46(2H、m)。
Embodiment 13
2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-methyl butanol hydrochloride
(13-1) synthetic (the compound 13-1) of (2-hydroxyl-1-methylol-1-methyl) ethyl carbamic acid tertiary butyl ester
Dissolving 2-amino-2-methyl-1 in methyl alcohol (200ml), ammediol hydrochloride (14.0g), the ice-cold N that adds down, N-diisopropylethylamine (46.3ml) and di-tert-butyl dicarbonic acid ester (43.7g), ice-cold stirring down 40 minutes was at room temperature stirred 27 hours again.The ice-cold 1M aqueous sodium hydroxide solution (100ml) that adds down stirred after 40 minutes in reaction solution, and methyl alcohol is heated up in a steamer in decompression.Add entry, behind ethyl acetate extraction, organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated, and obtains the title product (25.3g) of white powder.
1H-NMR(CDCl 3)δ(ppm)：1.17(3H、s)、1.44(9H、s)、3.45(2H、brs)、3.62(2H、dd、J＝7.1、11.3Hz)、3.78(2H、dd、J＝5.4、11.3Hz)、4.96(1H、brs)。
(13-2) synthetic (the compound 13-2) of (1-methylol-2-methoxymethoxy-1-methyl) ethyl carbamic acid tertiary butyl ester
In methylene dichloride (300ml) solution of compound 13-1 (25.3g), the ice-cold N that adds down, N-diisopropylethylamine (26.8ml) and methoxymethyl muriate (11.6ml), ice-cold stirring down 20 minutes was at room temperature stirred 22 hours again.In reaction solution, add entry, behind dichloromethane extraction, organic layer cleans in water, saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains is refining with silica gel chromatography, obtains the title product (14.2g) of colorless oil.
1H-NMR(CDCl 3)δ(ppm)：1.26(3H、s)、1.44(9H、s)、3.38(3H、s)、3.57(1H、d、J＝9.7Hz)、3.61(1H、dd、J＝7.8、11.5Hz)、3.66(1H、d、J＝9.7Hz)、3.71(1H、dd、J＝5.0、11.5Hz)、3.91(1H、brs)、4.64(2H、s)、5.10(1H、brs)。
(13-3) synthetic (the compound 13-3) of (1-formyl radical-2-methoxymethoxy-1-methyl) ethyl carbamic acid tertiary butyl ester
In the mixing solutions of the toluene (100ml) of compound 13-2 (14.2g) and Sodium Bromide (5.86g), vinyl acetic monomer (100ml), water (20ml); Ice-cold adding 2 down; 2; 6,6-tetramethyl piperidine-1-oxyradical (178mg), then water (150ml) solution of dropping 10% aqueous sodium hypochlorite solution (46.7g) and sodium hydrogencarbonate (13.8g) in 1.5 hours.Again ice-cold down stir 1.5 hours after, the separatory organic layer after cleaning in water, the saturated aqueous common salt, use anhydrous magnesium sulfate drying, reduces pressure to heat up in a steamer and desolvates, and obtains the title product (13.1g) of filbert oily thing.
1H-NMR(CDCl 3)δ(ppm)：1.39(3H、s)、1.45(9H、s)、3.34(3H、s)、3.75(2H、s)、4.60(2H、s)、5.39(1H、brs)、9.51(1H、s)。
(13-4) synthetic (the compound 13-4) of [3-(4-hydroxyl-3-trifluoromethyl)-1-(methoxymethoxy) methyl isophthalic acid-methyl] propyl carbamic acid tertiary butyl ester
Suspending reference example compound 2-5 (21.8g) in THF (200ml), the ice-cold tert.-butoxy potassium (4.35g) of adding down stirred 1 hour.THF (40ml) solution that in this mixing solutions, adds compound 13-3 (4.80g), ice-cold stirring down 1 and a half hours was at room temperature stirred 1 hour.Xiang Shuizhong adds reaction solution, and behind ethyl acetate extraction, organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains is refining with silica gel column chromatography, obtains colorless oil [3-(4-benzyloxy-3-trifluoromethyl)-1-(methoxymethoxy) methyl isophthalic acid-methyl] allyl amino formic acid tertiary butyl ester 8.45g.The geometrical isomer of the compound that obtains in addition, is than being (E: Z=3: 7).At 1 of this oily matter, add 10% year palladium gac in 4-diox (150ml) solution and (contain 50% moisture approximately, 845mg), under room temperature under the atmosphere of hydrogen gas, stirred 24 hours.Reaction solution through concentrating, obtains the title product (6.92g) of colorless oil after filtering with ferrite.
1H-NMR(CDCl 3)δ(ppm)：1.34(3H、s)、1.45(9H、s)、1.88-1.95(1H、m)、2.00-2.08(1H、m)、2.52-2.60(2H、m)、3.38(3H、s)、3.47(1H、d、J＝9.5Hz)、3.65(1H、d、J＝9.5Hz)、4.65(2H、s)、4.78(1H、brs)、5.98(1H、brs)、6.85(1H、d、J＝8.4Hz)、7.18(1H、dd、J＝1.5、8.4Hz)、7.29(1H、d、J＝1.5Hz)。
(13-5) synthetic (the compound 13-5) of [3-(4-oxygen in heptan base-3-trifluoromethyl)-1-(methoxymethoxy) methyl isophthalic acid-methyl] propyl carbamic acid tertiary butyl ester
At the N of compound 13-4 (1.5g), in dinethylformamide (15ml) solution, add salt of wormwood (1.53g) and n-heptyl bromide (0.63ml), stirred 6 hours down at 50 ℃.In water, add reaction solution, behind ethyl acetate extraction, organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying.This solvent is heated up in a steamer in decompression, obtains the title product (1.69g) of colorless oil.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.8Hz)、1.29-1.49(6H、m)、1.34(3H、s)、1.42-1.50(2H、m)、1.45(9H、s)、1.79(2H、quint、J＝6.9Hz)、1.84-1.95(1H、m)、2.00-2.08(1H、m)、2.54-2.61(2H、m)、3.38(3H、s)、3.49(1H、d、J＝9.5Hz)、3.64(1H、d、J＝9.5Hz)、4.00(2H、t、J＝6.5Hz)、4.64(2H、s)、4.72(1H、brs)、6.88(1H、d、J＝8.5Hz)、7.27(1H、dd、J＝1.9、8.5Hz)、7.35(1H、d、J＝1.9Hz)。
(13-6) synthetic (the compound 13-6) of 2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-methyl butanol hydrochloride
In ethanol (15ml) solution of compound 13-5 (1.69g), add concentrated hydrochloric acid (3ml), stirred 3 hours down at 50 ℃.In reaction solution, add 1M aqueous sodium hydroxide solution (50ml) and salt solution (50ml), use ethyl acetate extraction.Organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains is dissolved in the vinyl acetic monomer (50ml), adds 1M ether solution of hydrogen chloride (5ml), heats up in a steamer and desolvates.Residue joins in the ether, filters the solid separate out, and drying under reduced pressure obtains the title product (607mg) of white powder.
MS(ESI)m/z：362[M+H]
1H-NMR(DMSO-d 6)δ(ppm)：0.86(3H、t、J＝6.4Hz)、1.20(3H、s)、1.26-1.35(6H、m)、1.37-1.43(2H、m)、1.67-1.83(4H、m)、2.61(2H、t、J＝8.7Hz)、3.39(1H、dd、J＝4.6、11.2Hz)、3.46(1H、dd、J＝4.6、11.2Hz)、4.05(2H、t、J＝6.1Hz)、5.52(1H、t、J＝4.9Hz)、7.18(1H、d、J＝8.5Hz)、7.43-7.45(2H、m)、7.89(3H、brs)。
Embodiment 14
Mono phosphoric acid ester [2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-methylbutyl] ester
(14-1) synthetic (the compound 14-1) of [3-(4-oxygen in heptan base-3-trifluoromethyl)-1-methylol-1-methyl-propyl] carboxylamine tertiary butyl ester
In methyl alcohol (25ml) solution of compound 13-6 (841mg), add N, N-diisopropylethylamine (1.10ml) and di-tert-butyl dicarbonic acid ester (692mg) at room temperature stirred 24 hours.Behind the concentrating under reduced pressure reaction solution, add saturated sodium bicarbonate, use ethyl acetate extraction.Organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains is refining with silica gel column chromatography, obtains the title product (880mg) of colorless oil.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.8Hz)、1.22(3H、s)、1.28-1.39(6H、m)、1.44-1.49(11H、m)、1.79(2H、quint、J＝6.9Hz)、1.83-1.90(1H、m)、1.99-2.07(1H、m)、2.50-2.58(1H、m)、2.61-2.68(1H、m)、3.63-3.72(2H、m)、4.00(2H、t、J＝6.5Hz)、4.06(1H、brs)、4.63(1H、brs)、6.89(1H、d、J＝8.5Hz)、7.28(1H、dd、J＝1.7、8.5Hz)、7.36(1H、d、J＝1.7Hz)。
(14-2) synthetic (the compound 14-2) of [1-two (tertiary butyl) phosphinylidyne oxygen ylmethyl-3-(4-oxygen in heptan base-3-trifluoromethyl)-1-methyl-propyl] carboxylamine tertiary butyl ester
Acetonitrile (15ml) solution that in methylene dichloride (15ml) solution of compound 14-1 (870mg), adds 1H-tetrazolium (158mg).0 ℃ adds di-t-butyl diisopropylphosphoramidite (0.713ml) down in this mixed solution, ice-cold stirring down 1 and a half hours.Acetonitrile (15ml) solution and the di-t-butyl diisopropylphosphoramidite (0.713ml) that add 1H-tetrazolium (158mg) stirred 2 hours down ice-cold again.Between adding-and chloro perbenzoic acid (25% hydrate, 600mg), ice-cold stirring down 40 minutes.In reaction solution, add saturated sodium bicarbonate aqueous solution, behind chloroform extraction, organic layer cleans with saturated sodium bicarbonate aqueous solution, saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains is refining with silica gel column chromatography, obtains the title product (1.26g) of colorless oil.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.8Hz)、1.28-1.35(6H、m)、1.35(3H、s)、1.43(9H、s)、1.49(18H、s)、1.51-1.53(2H、m)、1.79(2H、quint、J＝6.9Hz)、1.86-1.94(1H、m)、2.03-2.11(1H、m)、2.52-2.62(2H、m)、3.86(1H、dd、J＝5.6、10.2Hz)、4.00(2H、t、J＝6.4Hz)、4.04(1H、dd、J＝5.5、10.2Hz)、4.85(1H、brs)、6.88(1H、d、J＝8.5Hz)、7.27(1H、dd、J＝1.8、8.5Hz)、7.35(1H、d、J＝1.8Hz)。
(14-3) synthetic (the compound 14-3) of mono phosphoric acid ester [2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-methylbutyl] ester
Dissolved compound 14-2 (1.24g) in ethanol (5ml) adds concentrated hydrochloric acid (1ml), stirs 1 hour down at 50 ℃.In reaction solution, add entry (30ml), the powder that leaching is separated out cleans through water and diethyl ether, obtains the title product (648mg) of white solid.
MS(ESI)m/z：442[M+H]
1H-NMR(CD 3OD)δ(ppm)：0.91(3H、t、J＝6.8Hz)、1.29-1.41(6H、m)、1.38(3H、s)、1.46-1.53(2H、m)、1.75-1.81(2H、m)、1.83-1.90(1H、m)、1.97-2.05(1H、m)、2.60-2.68(1H、m)、2.70-2.76(1H、m)、3.85(1H、dd、J＝5.4、11.4Hz)、3.94(1H、dd、J＝5.9、11.4Hz)、4.04(2H、t、J＝6.2Hz)、7.07(1H、d、J＝8.2Hz)、7.42-7.44(2H、m)。
Embodiment 15
(R)-2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-methyl butanol hydrochloride
(15-1) synthetic (the compound 15-1) of 2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-methyl butanol
In compound 13-6 (1.30g), add saturated sodium bicarbonate aqueous solution (100ml), use ethyl acetate extraction.Organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated, and obtains the title product (1.16g) of white waxy solid.
1H-NMR(DMSO-d 6)δ(ppm)：0.86(3H、t、J＝6.7Hz)、1.08(3H、s)、1.23-1.35(6H、m)、1.38-1.45(2H、m)、1.58-1.74(4H、m)、2.55-2.65(2H、m)、3.28(1H、d、J＝10.9Hz)、3.32(1H、d、J＝10.9Hz)、4.05(2H、t、J＝6.2Hz)、5.09(1H、brs)、5.52(2H、brs)、7.16(1H、d、J＝9.0Hz)、7.41-7.44(2H、m)。
(15-2) (R)-2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-methyl butanol (compound 15-2-1) and (S)-2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-methyl butanol (compound 15-2-2) is synthetic
Through using supercritical fluid chromatography (SFC) the separating compound 15-1 (2.63g) of CHIRALPAK (registered trademark) AD-H (carbonic acid gas/ethanol/diethylamine), obtain the white waxy solid of two enantiotropies respectively.The short first peak of RT is R body (0.91g, compound 15-2-1), and second peak that RT is long is S body (0.95g, compound 15-2-2).
(15-3) synthetic (the compound 15-3) of (R)-2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-methyl butanol hydrochloride
Suspended compound 15-2-1 (745mg) in vinyl acetic monomer (5ml), the vinyl acetic monomer solution (2ml) of adding 4M hydrogenchloride.And then add hexane (10ml), and to place after 1 hour, the solid that leaching is separated out obtains the title product (753mg) of white powder.
MS(ESI)m/z：362[M+H]
1H-NMR(DMSO-d 6)δ(ppm)：0.86(3H、t、J＝6.7Hz)、1.19(3H、s)、1.25-1.35(6H、m)、1.37-1.45(2H、m)、1.67-1.83(4H、m)、2.60(2H、t、J＝8.7Hz)、3.41-3.49(2H、m)、4.06(2H、t、J＝6.2Hz)、5.53(1H、t、J＝5.1Hz)、7.18(1H、d、J＝8.4Hz)、7.43-7.45(2H、m)、7.78(3H、brs)。
Embodiment 16
(R)-mono phosphoric acid ester [2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-methylbutyl] ester
Synthetic (the compound 16-1) of (16-1) (R)-[3-(4-oxygen in heptan base-3-trifluoromethyl)-1-methylol-1-methyl-propyl] carboxylamine tertiary butyl ester
In methyl alcohol (10ml) solution of compound 15-2-1 (120mg), add N, N-diisopropylethylamine (0.117ml) and di-tert-butyl dicarbonic acid ester (109mg) at room temperature stirred 24 hours.In reaction solution, add saturated sodium bicarbonate, heat up in a steamer methyl alcohol under the decompression, behind the residue dilute with water that obtains, use ethyl acetate extraction.Organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains is refining with silica gel column chromatography, obtains the title product (159mg) of colorless oil.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.7Hz)、1.22(3H、s)、1.28-1.38(6H、m)、1.42-1.50(11H、m)、1.79(2H、quint、J＝6.9Hz)、1.83-1.90(1H、m)、1.99-2.07(1H、m)、2.50-2.58(1H、m)、2.61-2.68(1H、m)、3.63-3.72(2H、m)、4.00(2H、t、J＝6.4Hz)、4.03(1H、brs)、4.62(1H、brs)、6.89(1H、d、J＝8.5Hz)、7.28(1H、dd、J＝1.6、8.5Hz)、7.36(1H、d、J＝1.6Hz)。
(16-2) (R)-mono phosphoric acid ester [2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-methylbutyl] ester (compound 16-2)
In methylene dichloride (5ml) solution of compound 16-1 (159mg), add 1H-tetrazolium (2
7.9mg) acetonitrile (5ml) solution.0 ℃ adds di-t-butyl diisopropylphosphoramidite (0.126ml) down in this mixed solution, ice-cold stirring down 1 hour.Add 1H-tetrazolium (27.9mg) and di-t-butyl diisopropylphosphoramidite (0.126ml), and then stirred 1 hour down ice-cold.Add 1H-tetrazolium (55.8mg) and di-t-butyl diisopropylphosphoramidite (0.252ml), stirred 1 hour down ice-cold again.Between adding-and chloro perbenzoic acid (25% hydrate, 106mg), ice-cold stirring down 20 minutes.Between adding-and chloro perbenzoic acid (25% hydrate, 106mg), stirred 30 minutes down ice-cold again.In reaction solution, add sodium bicarbonate aqueous solution, behind dichloromethane extraction, organic layer cleans with saturated sodium bicarbonate aqueous solution, saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains is refining with silica gel column chromatography, is mainly contained (R)-colorless oil (271mg) of [1-two (tertiary butyl) phosphinylidyne oxygen ylmethyl-3-(4-oxygen in heptan base-3-trifluoromethyl)-1-methyl-propyl] carboxylamine tertiary butyl ester.This oily matter is dissolved in the ethanol (10ml), adds concentrated hydrochloric acid (3ml), stirs 3 hours down at 50 ℃.In reaction solution, add entry (50ml), the powder that leaching is separated out, water and diethyl ether clean, and obtain the title product (81.9mg) of white powder.
MS(ESI)m/z：442[M+H]
1H-NMR(CD 3OD)δ(ppm)：0.91(3H、t、J＝6.8Hz)、1.29-1.41(6H、m)、1.37(3H、s)、1.45-1.53(2H、m)、1.75-1.81(2H、m)、1.82-1.90(1H、m)、1.96-2.04(1H、m)、2.60-2.67(1H、m)、2.69-2.77(1H、m)、3.85(1H、dd、J＝5.3、11.4Hz)、3.94(1H、dd、J＝5.9、11.4Hz)、4.04(2H、t、J＝6.2Hz)、7.07(1H、d、J＝8.1Hz)、7.42-7.44(2H、m)。
Embodiment 17
(S)-2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-methyl butanol hydrochloride
(17-1) synthetic (the compound 17-1) of (S)-2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-methyl butanol hydrochloride
Suspended compound 15-2-2 (785mg) in vinyl acetic monomer (5ml), the vinyl acetic monomer solution (2ml) of adding 4M hydrogenchloride.Add hexane (10ml) again, place after 1 hour, the solid that leaching is separated out obtains the title product (833mg) of white powder.
MS(ESI)m/z：362[M+H]
1H-NMR(DMSO-d 6)δ(ppm)：0.86(3H、t、J＝6.7Hz)、1.20(3H、s)、1.25-1.35(6H、m)、1.37-1.45(2H、m)、1.67-1.83(4H、m)、2.60(2H、t、J＝8.7Hz)、3.41-3.49(2H、m)、4.06(2H、t、J＝6.2Hz)、5.53(1H、t、J＝5.0Hz)、7.18(1H、d、J＝8.5Hz)、7.44-7.46(2H、m)、7.84(3H、brs)。
Embodiment 18
(S)-mono phosphoric acid ester [2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-methylbutyl] ester
Synthetic (the compound 18-1) of (18-1) (S)-[3-(4-oxygen in heptan base-3-trifluoromethyl)-1-methylol-1-methyl-propyl] carboxylamine tertiary butyl ester
In methyl alcohol (10ml) solution of compound 15-2-2 (120mg), add N, N-diisopropylethylamine (0.117ml) and di-tert-butyl dicarbonic acid ester (109mg) at room temperature stirred 24 hours.In reaction solution, add saturated sodium bicarbonate, heat up in a steamer methyl alcohol under the decompression, behind the residue dilute with water that obtains, use ethyl acetate extraction.Organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains is refining with silica gel column chromatography, obtains the title product (139mg) of colorless oil.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.7Hz)、1.22(3H、s)、1.28-1.38(6H、m)、1.42-1.50(11H、m)、1.79(2H、quint、J＝6.9Hz)、1.83-1.90(1H、m)、1.99-2.07(1H、m)、2.51-2.58(1H、m)、2.61-2.69(1H、m)、3.63-3.72(2H、m)、4.00(2H、t、J＝6.3Hz)、4.02(1H、brs)、4.63(1H、brs)、6.89(1H、d、J＝8.4Hz)、7.28(1H、dd、J＝1.7、8.4Hz)、7.36(1H、d、J＝1.7Hz)。
(18-2) (R)-mono phosphoric acid ester [2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-methylbutyl] ester (compound 18-2)
Acetonitrile (5ml) solution that in methylene dichloride (5ml) solution of compound 18-1 (139mg), adds 1H-tetrazolium (27.9mg).0 ℃ adds di-t-butyl diisopropylphosphoramidite (0.126ml) down in this mixed solution, ice-cold stirring down 1 hour.Add 1H-tetrazolium (27.9mg) and di-t-butyl diisopropylphosphoramidite (0.126ml), stirred 40 minutes down ice-cold again.Add 1H-tetrazolium (55.8mg) and di-t-butyl diisopropylphosphoramidite (0.252ml), stirred 50 minutes down ice-cold again.Between adding-and chloro perbenzoic acid (25% hydrate, 106mg), ice-coldly 20 stir minute down.Between adding-and chloro perbenzoic acid (25% hydrate, 106mg), stirred 50 minutes down ice-cold again.In reaction solution, add sodium bicarbonate aqueous solution, behind dichloromethane extraction, organic layer cleans with saturated sodium bicarbonate aqueous solution, saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains is refining with silica gel column chromatography, is mainly contained (S)-colorless oil (260mg) of [1-two (tertiary butyl) phosphinylidyne oxygen ylmethyl-3-(4-oxygen in heptan base-3-trifluoromethyl)-1-methyl-propyl] carboxylamine tertiary butyl ester.This oily matter of dissolving adds concentrated hydrochloric acid (3ml) in ethanol (10ml), stirs 3 hours down at 50 ℃.In reaction solution, add entry (50ml), the powder that leaching is separated out, water and diethyl ether clean, and obtain the title product (63.0mg) of white powder.
MS(ESI)m/z：442[M+H]
1H-NMR(CD 3OD)δ(ppm)：0.91(3H、t、J＝6.8Hz)、1.29-1.41(6H、m)、1.37(3H、s)、1.45-1.53(2H、m)、1.75-1.81(2H、m)、1.82-1.90(1H、m)、1.96-2.04(1H、m)、2.60-2.76(2H、m)、3.85(1H、dd、J＝5.3、11.4Hz)、3.94(1H、dd、J＝5.9、11.4Hz)、4.04(2H、t、J＝6.2Hz)、7.07(1H、d、J＝8.1Hz)、7.42-7.44(2H、m)。
Embodiment 19
2-amino-2-ethyl-4-(4-oxygen in heptan base-3-trifluoromethyl) Kauri-butanol hydrochloric salt
(19-1) synthetic (the compound 19-1) of [1, two (methylol) propyl group of 1-] carboxylamine tertiary butyl ester
At 2-amino-2-ethyl-1, ammediol (22.0g) and N, in methyl alcohol (500ml) solution of N-diisopropylethylamine (64.3ml), the ice-cold di-tert-butyl dicarbonic acid ester (60.5g) that adds down, ice-cold stirring down 40 minutes was at room temperature stirred 16 hours again.The ice-cold 1M aqueous sodium hydroxide solution (184ml) that adds down stirred after 40 minutes in reaction solution, removed methyl alcohol under the decompression.Add entry, behind ethyl acetate extraction, organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated, and obtains the title product (41.0g) of colorless oil.。
1H-NMR(CDCl 3)δ(ppm)：0.90(3H、t、J＝7.5Hz)、1.45(9H、s)、1.59(2H、q、J＝7.5Hz)、3.45(2H、brs)、3.60(2H、dd、J＝6.9、11.6Hz)、3.84(2H、dd、J＝4.8、11.6Hz)、4.89(1H、brs)。
(19-2) synthetic (the compound 19-2) of [1-methylol-1-(methoxymethoxy) methyl] propyl carbamic acid tertiary butyl ester
In methylene dichloride (400ml) solution of compound 19-1 (41.0g), the ice-cold N that adds down, N-diisopropylethylamine (40.7ml) and methoxymethyl muriate (17.6ml), ice-cold stirring down 40 minutes was at room temperature stirred 4 hours again.In reaction solution, add entry, behind dichloromethane extraction, organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains is refining with silica gel chromatography, obtains the title product (21.3g) of colorless oil.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝7.5Hz)、1.44(9H、s)、1.55-1.62(1H、m)、1.75-1.84(1H、m)、3.38(3H、s)、3.49(1H、d、J＝9.8Hz)、3.68(2H、d、J＝6.6Hz)、3.74(1H、d、J＝9.8Hz)、4.04(1H、brs)、4.63(2H、s)、5.05(1H、brs)。
(19-3) synthetic (the compound 19-3) of [1-formyl radical-1-(methoxymethoxy) methyl] propyl carbamic acid tertiary butyl ester
In the mixing solutions of the toluene (170ml) of compound 19-2 (21.3g) and Sodium Bromide (8.32g), vinyl acetic monomer (170ml), water (30ml); Ice-cold adding 2 down; 2; 6,6-tetramethyl piperidine-1 oxyradical (253mg), then water (200ml) solution of dropping 10% aqueous sodium hypochlorite solution (66.3g) and sodium hydrogencarbonate (19.6g) in 1.5 hours.After 1.5 hours, in 30 minutes, drip water (67ml) solution of 10% aqueous sodium hypochlorite solution (22.1g) and sodium hydrogencarbonate (6.53g), restir 30 minutes in ice-cold stirring down again.With the organic layer separatory, after vinyl acetic monomer (200ml) dilution, organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated, and obtains the title product (22.0g) of filbert oily thing.
1H-NMR(CDCl 3)δ(ppm)：0.81(3H、t、J＝7.5Hz)、1.45(9H、s)、1.74-1.83(1H、m)、2.04-2.11(1H、m)、3.32(3H、s)、3.81(1H、d、J＝10.0Hz)、4.03(1H、d、J＝10.0Hz)、4.59(2H、s)、5.37(1H、brs)、9.39(1H、s)。
(19-4) synthetic (the compound 19-4) of [1-ethyl-3-(4-hydroxyl-3-trifluoromethyl)-1-(methoxymethoxy) methyl] propyl carbamic acid tertiary butyl ester
Suspending reference example compound 2-5 (26.3g) in THF (120ml), the ice-cold tert.-butoxy potassium (5.24g) of adding down stirred 50 minutes.THF (80ml) solution that in this mixing solutions, adds compound 19-3 (6.10g), ice-cold stirring down 2 hours was at room temperature stirred 4 hours.Reaction solution joins in the salt solution, and behind ethyl acetate extraction, organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains is refining with silica gel column chromatography, obtains colorless oil [1-ethyl-3-(4-benzyloxy-3-trifluoromethyl)-1-(methoxymethoxy) methyl] allyl amino formic acid tertiary butyl ester 10.3g.The geometrical isomer of the compound that obtains in addition, is than being (E: Z=1: 2.8).At 1 of this oily matter, add 10% year palladium gac (containing 50% moisture, 2g approximately) in 4-diox (200ml) solution, under room temperature under the atmosphere of hydrogen gas, stirred 9 hours.Reaction solution concentrates after filtering with ferrite, obtains the title product (8.67g) of white powder.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝7.5Hz)、1.45(9H、s)、1.65-1.74(1H、m)、1.76-1.86(1H、m)、1.93-1.97(2H、m)、2.52-2.56(2H、m)、3.39(3H、s)、3.57(1H、d、J＝9.7Hz)、3.63(1H、d、J＝9.7Hz)、4.64(3H、m)、5.85(1H、brs)、6.85(1H、d、J＝8.3Hz)、7.20(1H、brd、J＝8.3Hz)、7.29(1H、d、J＝1.4Hz)。
(19-5) synthetic (the compound 19-5) of [1-ethyl-3-(4-oxygen in heptan base-3-trifluoromethyl)-1-(methoxymethoxy) methyl] propyl carbamic acid tertiary butyl ester
At the N of compound 19-4 (1.5g), add salt of wormwood (1.48g) and n-heptyl bromide (0.61ml) in dinethylformamide (15ml) solution, stirred 6 hours down at 50 ℃.In water, add reaction solution, behind ethyl acetate extraction, organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying.This solvent is heated up in a steamer in decompression, obtains colorless oil title product (1.83g).
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.4Hz)、0.89(3H、t、J＝7.6Hz)、1.28-1.38(6H、m)、1.42-1.49(11H、m)、1.68-1.88(4H、m)、1.92-1.97(2H、m)、2.52-2.57(2H、m)、3.38(3H、s)、3.57(1H、d、J＝9.7Hz)、3.63(1H、d、J＝9.7Hz)、4.00(2H、t、J＝6.4Hz)、4.60(1H、brs)、4.64(2H、s)、6.88(1H、d、J＝8.5Hz)、7.27(1H、dd、J＝1.6、8.5Hz)、7.35(1H、d、J＝1.6Hz)。
(19-6) synthetic (the compound 19-6) of 2-amino-2-ethyl-4-(4-oxygen in heptan base-3-trifluoromethyl) Kauri-butanol hydrochloric salt
In ethanol (15ml) solution of compound 19-5 (1.83g), add concentrated hydrochloric acid (3ml), stirred 4 hours down at 50 ℃.Add 1M aqueous sodium hydroxide solution (100ml) in the reaction solution, use ethyl acetate extraction.Organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains is dissolved in the vinyl acetic monomer (30ml), adds 1M ether solution of hydrogen chloride (10ml), heats up in a steamer and desolvates.Add diethyl ether and hexane at residue, the solid that leaching is separated out, drying obtains the title product (1.22g) of white powder.
MS(ESI)m/z：376[M+H]
1H-NMR(DMSO-d 6)δ(ppm)：0.86(3H、t、J＝6.4Hz)、0.90(3H、t、J＝7.4Hz)、1.25-1.35(6H、m)、1.37-1.45(2H、m)、1.57-1.65(2H、m)、1.67-1.77(4H、m)、2.56-2.61(2H、m)、3.43-3.51(2H、m)、4.06(2H、t、J＝6.2Hz)、5.49(1H、t、J＝5.0Hz)、7.18(1H、d、J＝9.2Hz)、7.45-7.46(2H、m)、7.90(3H、brs)。
Embodiment 20
Mono phosphoric acid ester [2-amino-2-ethyl-4-(4-oxygen in heptan base-3-trifluoromethyl) butyl] ester
(20-1) synthetic (the compound 20-1) of [1-ethyl-3-(4-oxygen in heptan base-3-trifluoromethyl)-1-methylol propyl group] carboxylamine tertiary butyl ester
In methyl alcohol (25ml) solution of compound 19-6 (1.04g), add N, N-diisopropylethylamine (1.32ml) and di-tert-butyl dicarbonic acid ester (825mg) at room temperature stirred 13 hours.Behind the concentrating under reduced pressure reaction solution, add saturated sodium bicarbonate, use ethyl acetate extraction.Organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains is refining with silica gel column chromatography, obtains colorless oil title product (1.21g).
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.8Hz)、0.93(3H、t、J＝7.5Hz)、1.28-1.39(6H、m)、1.42-1.49(11H、m)、1.64(2H、q、J＝7.5Hz)、1.79(2H、quint、J＝7.0Hz)、1.82-1.94(2H、m)、2.46-2.54(1H、m)、2.56-2.64(1H、m)、3.72(2H、d、J ＝6.3Hz)、4.00(2H、t、J＝6.5Hz)、4.09(1H、brs)、4.57(1H、brs)、6.89(1H、d、J＝8.5Hz)、7.28(1H、dd、J＝1.7、8.5Hz)、7.35(1H、d、J＝1.7Hz)。
(20-2) synthetic (the compound 20-2) of [1-two (tertiary butyl) phosphinylidyne oxygen ylmethyl-1-ethyl-3-(4-oxygen in heptan base-3-trifluoromethyl) propyl group] carboxylamine tertiary butyl ester
Acetonitrile (15ml) solution that in methylene dichloride (15ml) solution of compound 20-1 (1.20g), adds 1H-tetrazolium (212mg).0 ℃ adds di-t-butyl diisopropylphosphoramidite (0.956ml) down in this mixed solution, ice-cold stirring down 1 hour.Acetonitrile (15ml) solution and the di-t-butyl diisopropylphosphoramidite (0.478ml) that add 1H-tetrazolium (106mg) stirred 1 hour down ice-cold again.Between adding-and chloro perbenzoic acid (25% hydrate, 804mg), ice-cold stirring down 50 minutes.Add saturated sodium bicarbonate aqueous solution at reaction solution, behind chloroform extraction, organic layer cleans with saturated sodium bicarbonate aqueous solution, saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains is refining with silica gel column chromatography, obtains the title product (1.56g) of colorless oil.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.8Hz)、0.90(3H、t、J＝7.3Hz)、1.28-1.38(6H、m)、1.43(9H、s)、1.47-1.51(2H、m)、1.49(18H、s)、1.70-1.82(4H、m)、1.86-2.01(2H、m)、2.53-2.59(2H、m)、3.95-4.06(4H、m)、4.67(1H、brs)、6.88(1H、d、J＝8.5Hz)、7.28(1H、dd、J＝1.7、8.5Hz)、7.35(1H、brs)。
(20-3) synthetic (the compound 20-3) of mono phosphoric acid ester [2-amino-2-ethyl-4-(4-oxygen in heptan base-3-trifluoromethyl) butyl] ester
Dissolved compound 20-2 (1.55g) in ethanol (5ml) adds concentrated hydrochloric acid (1ml), stirs 1 hour down at 50 ℃.In reaction solution, add entry (50ml), the powder that leaching is separated out, water and diethyl ether clean, and obtain the title product (907mg) of white powder.
MS(ESI)m/z：456[M+H]
1H-NMR(CD 3OD)δ(ppm)：0.91(3H、t、J＝6.7Hz)、1.03(3H、t、J＝7.5Hz)、1.30-1.40(6H、m)、1.49(2H、quint、J＝7.5Hz)、1.73-2.01(6H、m)、2.57-2.74(2H、m)、3.88-3.96(2H、m)、4.05(2H、t、J＝6.2Hz)、7.08(1H、d、J＝8.9Hz)、7.42-7.44(2H、m)。
Embodiment 21
2-amino-2-[2-(4-oxygen in heptan base-3-trifluoromethyl) ethyl] butane-1, the 4-diol hydrochloride
(21-1) synthetic (the compound 21-1) of 2-[(tertbutyloxycarbonyl) amino]-2-[2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) ethyl] ethyl malonate
Dissolving (tertbutyloxycarbonyl) amidomalonic acid diethyl ester (52.3g) in THF (400ml); Add sodium tert.-butoxy thing (19.2g); THF (100ml) solution that under 70 ℃, in reaction solution, adds 2-(2-bromine oxethyl) tetrahydrochysene-2H-pyrans (40.4g) stirs heating down 10 hours.Behind the cooling reaction liquid, add in the saturated aqueous common salt.After the extraction of vinyl acetic monomer separatory, organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying.Decompression is heated up in a steamer and is desolvated, and the residue that obtains is refining with silica gel column chromatography, obtains the title product (50.0g) of colorless oil.
1H-NMR(CDCl 3)δ(ppm)：1.30(6H、t、J＝7.1Hz)、1.45(9H、s)、1.45-1.55(4H、m)、1.58-1.78(2H、m)、2.60-2.64(2H、m)、3.35-3.41(1H、m)、3.46-3.50(1H、m)、3.77-3.84(2H、m)、4.12-4.28(4H、m)、4.49-4.51(1H、m)、6.08(1H、brs)。
(21-2) 1, synthetic (the compound 21-2) of two (the methylol)-3-of 1-(tetrahydrochysene-2H-pyrans-2-base oxygen base) propyl carbamic acid tertiary butyl ester
Dissolved compound 21-1 (50.0g) in the mixing solutions of ethanol (530ml), THF (130ml) and water (260ml).0 ℃ adds calcium chloride (27.5g) down in this solution, then adds Peng Qinghuana (18.8g) in batches, and uniform temp stirs after 2 hours down, and restir is 18 hours under the room temperature.Behind the concentrating under reduced pressure reaction solution, join in the saturated aqueous ammonium chloride (3l), extract with the vinyl acetic monomer separatory.Organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying.Decompression is heated up in a steamer and is desolvated, and the residue that obtains is refining with silica gel chromatography, obtains the title product (21.6g) of colorless oil.
1H-NMR(CDCl 3)δ(ppm)：1.43(9H、s)、1.53-1.62(4H、m)、1.71-1.83(2H、m)、1.95(1H、ddd、J＝15.3、8.0、2.8Hz)、2.02(1H、ddd、J＝15.3、7.4、2.8Hz)、3.46-3.59(4H、m)、3.69-3.73(2H、m)、3.82-3.88(1H、m)、3.91-3.96(1H、m)、4.13(2H、brs)、4.60-4.62(1H、m)、5.79(1H、brs)。
(21-3) synthetic (the compound 21-3) of 1-methylol-1-(methoxymethoxy) methyl-3-(tetrahydrochysene-2H-pyrans-2-base oxygen base) propyl carbamic acid tertiary butyl ester
In methylene dichloride (250ml) solution of compound 21-2 (21.6g), the ice-cold N that adds down, N-diisopropylethylamine (14.7ml) and methoxymethyl muriate (6.37ml), ice-cold stirring down 1 and a half hours was at room temperature stirred 17 hours again.In reaction solution, add entry, behind dichloromethane extraction, organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains is refining with silica gel chromatography, obtains the title product (9.61g) of colorless oil.
1H-NMR(CDCl 3)δ(ppm)：1.42(9H、s)、1.51-1.63(4H、m)、1.68-1.93(3H、m)、2.03-2.10(1H、m)、3.37(3H、s)、3.51-3.60(3H、m)、3.69-4.00(5H、m)、4.26、4.35(1H、2×brs)、4.61-4.66(3H、m)、5.61、5.75(1H、2×brs)。
(21-4) synthetic (the compound 21-4) of 1-formyl radical-1-(methoxymethoxy) methyl-3-(tetrahydrochysene-2H-pyrans-2-base oxygen base) propyl carbamic acid tertiary butyl ester
In the mixing solutions of the toluene (50ml) of compound 21-3 (9.59g) and Sodium Bromide (2.72g), vinyl acetic monomer (50ml), water (9ml); Ice-cold adding 2 down; 2; 6,6-tetramethyl piperidine-1-oxyradical (82.5mg), then water (75ml) solution of dropping 10% aqueous sodium hypochlorite solution (21.7g) and sodium hydrogencarbonate (3.19g) in 2 hours.After 2 hours, in 20 minutes, drip water (35ml) solution of 10% aqueous sodium hypochlorite solution (10.9g) and sodium hydrogencarbonate (3.19g), restir 20 minutes in ice-cold stirring down again.With the organic layer separatory, after vinyl acetic monomer (200ml) dilution, organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated, and obtains the title product (8.54g) of brown oil.
1H-NMR(CDCl 3)δ(ppm)：1.44(9H、s)、1.45-1.78(6H、m)、2.10-2.18(1H、m)、2.35-2.46(1H、m)、3.31、3.32(3H、2×s)、3.33-3.41(1H、m)、3.47-3.51(1H、m)、3.67-3.74(1H、m)、3.77-3.84(2H、m)、4.05-4.13(1H、m)、4.43-4.45、4.56-4.58(1H、2×m)、4.58、4.58(2H、2×s)、5.72、5.74(1H、2×brs)、9.40、9.44(1H、2×s)。
(21-5) synthetic (the compound 21-5) of 3-(4-benzyloxy-3-trifluoromethyl)-1-(methoxymethoxy) methyl isophthalic acid-[2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) ethyl] propyl carbamic acid tertiary butyl ester
Suspending reference example compound 2-5 (10.9g) in THF (80ml), the ice-cold tert.-butoxy potassium (2.17g) of adding down stirred 30 minutes.THF (25ml) solution that in this mixing solutions, adds compound 21-4 (3.50g), ice-cold stirring down 20 minutes was at room temperature stirred 5 hours again.Reaction solution joins in the salt solution, and behind ethyl acetate extraction, organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains is refining with silica gel column chromatography, obtains 3-(4-benzyloxy-3-trifluoromethyl)-1-(methoxymethoxy) methyl isophthalic acid-[2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) ethyl] allyl amino formic acid tertiary butyl ester of the faint yellow oily thing of 4.95g.The geometrical isomer of the compound that obtains in addition, is than being (E: Z=1: 3).In toluene (200ml) solution of this oily matter, add chloro three (triphenylphosphine) rhodium (I) (5.0g), 60 ℃ were stirred 19 hours down under atmosphere of hydrogen gas.Add chloro three (triphenylphosphine) rhodium (I) (2.5g), 60 ℃ were stirred 10 hours down under atmosphere of hydrogen gas.Reaction solution concentrates after filtering with ferrite.The residue that obtains is refining with silica gel column chromatography, obtains the title product (4.95g) of yellow oil.
1H-NMR(CDCl 3)δ(ppm)：1.43(9H、s)、1.51-1.64(4H、m)、1.67-1.75(1H、m)、1.79-1.88(1H、m)、1.92-2.28(4H、m)、2.54-2.62(2H、m)、3.36、3.37(3H、2×s)、3.46-3.59(2H、m)、3.71-3.78(2H、m)、3.82-4.03(2H、m)、4.60-4.64(3H、m)、5.15(2H、s)、5.41、5.55(1H、2×brs)、6.93(1H、d、J＝8.5Hz)、7.26-7.32(2H、m)、7.36-7.44(5H、m)。
(21-6) synthetic (the compound 21-6) of 3-(4-hydroxyl-3-trifluoromethyl)-1-(methoxymethoxy) methyl isophthalic acid-[2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) ethyl] propyl carbamic acid tertiary butyl ester
At 1 of compound 21-5 (4.94g), add 1 in 4-diox (150ml) solution
0% year palladium gac (containing 50% moisture, 2g approximately) stirred 22 hours under atmosphere of hydrogen gas.Reaction solution through concentrating, obtains the title product (4.07g) of colorless oil after filtering with ferrite.
1H-NMR(CDCl 3)δ(ppm)：1.43(9H、s)、1.52-1.64(4H、m)、1.68-1.75(1H、m)、1.79-1.88(1H、m)、1.92-2.27(4H、m)、2.55-2.61(2H、m)、3.36、3.37(3H、2×s)、3.46-3.60(2H、m)、3.71-4.03(4H、m)、4.61-4.63(3H、m)、5.45、5.59(1H、2×brs)、5.54(1H、brs)、6.85(1H、d、J＝8.4Hz)、7.21-7.23(1H、m)、7.30(1H、brs)。
(21-7) synthetic (the compound 21-7) of 3-(4-oxygen in heptan base-3-trifluoromethyl)-1-(methoxymethoxy) methyl isophthalic acid-[2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) ethyl] propyl carbamic acid tertiary butyl ester
At N, dissolved compound 21-6 (1.24g) in the dinethylformamide (20ml) adds salt of wormwood (986mg), n-heptyl bromide (0.458ml), stirs 2 and a half hours down at 80 ℃.In reaction solution, add entry, behind ethyl acetate extraction, in water, saturated aqueous common salt, clean, use anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated, and obtains the title product (1.49g) of faint yellow oily thing.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.8Hz)、1.25-1.40(7H、m)、1.40-1.49(2H、m)、1.43(9H、s)、1.50-1.68(3H、m)、1.69-1.90(4H、m)、1.91-2.00(2H、m)、2.00-2.20(2H、m)、2.56-2.61(2H、m)、3.36、3.37(3H、2×s)、3.45-3.60(2H、m)、3.71-3.96(4H、m)、4.00(2H、t、J＝6.4Hz)、4.61-4.63(3H、m)、5.40、5.57(1H、2×brs)、6.88(1H、d、J＝8.5Hz)、7.28(1H、brs)、7.36(1H、brs)。
(21-8) 2-amino-2-[2-(4-oxygen in heptan base-3-trifluoromethyl) ethyl] butane-1, synthetic (the compound 21-8) of 4-diol hydrochloride
Dissolved compound 21-7 (1.49g) in ethanol (20ml) adds concentrated hydrochloric acid (3ml), stirs 1 and a half hours down at 80 ℃.Concentration of reaction solution, residue cleans with diethyl ether, obtains the title product (915mg) of white powder.
MS(ESI)m/z：392[M+H]
1H-NMR(DMSO-d 6)δ(ppm)：0.86(3H、t、J＝6.8Hz)、1.25-1.34(6H、m)、1.35-1.45(2H、m)、1.68-1.78(2H、m)、1.79-1.83(4H、m)、2.59-2.65(2H、m)、3.51(2H、d、J＝4.4Hz)、3.60(2H、t、J＝6.4Hz)、4.05(2H、t、J＝6.2Hz)、5.45(1H、t、J＝4.8Hz)、7.18(1H、d、J＝9.2Hz)、7.43-7.46(2H、m)、7.75(3H、brs)。
Embodiment 22
2-amino-4-fluoro-2-[2-(4-oxygen in heptan base-3-trifluoromethyl) ethyl] Kauri-butanol hydrochloric salt
(22-1) synthetic (the compound 22-1) of 4-(2-fluoro ethyl)-4-[2-(4-oxygen in heptan base-3-trifluoromethyl) ethyl]-2-methyl-2-oxazoline
At the N of compound 21-8 (830mg), in dinethylformamide (20ml) solution, add N, N-diisopropylethylamine (1.04ml), former acetic acid triethyl (0.368ml) stirred 5 hours down at 120 ℃.In reaction solution, add entry, behind ethyl acetate extraction, in water, saturated aqueous common salt, clean, use anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated, and obtains the 840mg brown oil.In THF (30ml) solution of this brown oil; Add molecular sieve
Figure S2006800472557D00841
(8.4g), p-toluenesulfonyl fluorochemical (690mg) and 1M-TBuA fluorochemical/tetrahydrofuran solution (5.82ml), the reflux diel.Behind the filtering reacting liquid, in filtrating, add the 1M aqueous hydrochloric acid.Behind ethyl acetate extraction, clean with saturated sodium bicarbonate aqueous solution, saturated aqueous common salt, use anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated.The residue that obtains is with silica gel column chromatography (hexane: vinyl acetic monomer=1: 2～1: 3) make with extra care, obtain the title product (400mg) of brown oil.
1H-NMR(DMSO-d 6)δ(ppm)：0.86-0.94(3H、m)、1.25-1.40(6H、m)、1.41-1.51(2H、m)、1.76-1.95(4H、m)、1.97-2.08(2H、m)、2.01(3H、s)、2.50-2.66(2H、m)、4.00(2H、t、J＝6.2Hz)、4.06(1H、d、J＝8.8Hz)、4.14(1H、d、J＝8.8Hz)、4.53(1H、dd、J＝48、3.8Hz)、4.65(1H、dd、J＝48、3.8Hz)、6.89(1H、d、J＝8.4Hz)、7.26(1H、brs)、7.36(1H、brs)。
(22-2) synthetic (the compound 22-2) of 2-amino-4-fluoro-2-[2-(4-oxygen in heptan base-3-trifluoromethyl) ethyl] Kauri-butanol hydrochloric salt
Dissolved compound 22-1 (400mg) in ethanol (10ml) adds concentrated hydrochloric acid (2ml), stirs 4 and a half hours down at 70 ℃.Concentration of reaction solution, residue cleans with Di Iso Propyl Ether, obtains the title product (360mg) of white powder.
MS(ESI)m/z：394[M+H]
1H-NMR(DMSO-d 6)δ(ppm)：0.86(3H、t、J＝6.7Hz)、1.24-1.38(6H、m)、1.39-1.46(2H、m)、1.68-1.78(2H、m)、1.79-1.86(2H、m)、2.04(1H、t、J＝6.0Hz)、2.10(1H、t、J＝6.0Hz)、2.59-2.66(2H、m)、3.53(2H、d、J＝5.0Hz)、4.06(2H、t、J＝6.2Hz)、4.61(1H、dt、J＝47、6.0Hz)、4.73(1H、dt、J＝47、6.0Hz)、5.56(1H、t、J＝5.0Hz)、7.18(1H、d、J＝8.4Hz)、7.42-7.45(2H、m)、8.09(3H、brs)。
Embodiment 23
Mono phosphoric acid ester [2-amino-2-(2-fluoro ethyl)-4-(4-oxygen in heptan base-3-trifluoromethyl) butyl] ester
(23-1) synthetic (the compound 23-1) of [1-two (tertiary butyl) phosphinylidyne oxygen ylmethyl-1-(2-fluoro ethyl)-3-(4-oxygen in heptan base-3-trifluoromethyl) propyl group] carboxylamine tertiary butyl ester
In methyl alcohol (15ml) solution of compound 22-2 (290mg), add triethylamine (0.284ml) and di-tert-butyl dicarbonic acid ester (220mg), at room temperature stirred 18 hours.Add di-tert-butyl dicarbonic acid ester (220mg) again, at room temperature stirred 5 hours.Behind the concentrating under reduced pressure reaction solution, add entry, use ethyl acetate extraction.Organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated, and obtains the faint yellow oily thing of 400mg.In the solution of the methylene dichloride (5ml) of this faint yellow oily thing (400mg) and acetonitrile (2ml), add 1H-tetrazolium (94mg), di-t-butyl diethylammonium phosphoramidite (0.401ml), at room temperature stirred 2 hours.Ice-cold reaction soln, (5-6M 0.402ml), at room temperature stirred 30 minutes to add the decane solution that contains tert-butyl hydroperoxide.In reaction solution, add saturated sodium bicarbonate aqueous solution, behind chloroform extraction, organic layer is used anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains is with silica gel column chromatography (hexane: vinyl acetic monomer=1: 1～1: 2) make with extra care, obtain the title product (530mg) of colorless oil.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.8Hz)、1.29-1.40(6H、m)、1.41-1.50(2H、m)、1.43(9H、s)、1.49(18H、s)、1.75-1.81(2H、m)、1.90-2.01(2H、m)、2.10-2.25(2H、m)、2.61(2H、t、J＝8.6Hz)、4.03(2H、t、J＝6.2Hz)、4.04-4.18(2H、m)、4.55(1H、dt、J＝47、5.8Hz)、4.66(1H、dt、J＝47、5.8Hz)、7.37(1H、d、J＝8.4Hz)、7.34-7.37(2H、m)。
(23-2) synthetic (the compound 23-2) of mono phosphoric acid ester [2-amino-2-(2-fluoro ethyl)-4-(4-oxygen in heptan base-3-trifluoromethyl) butyl] ester
Dissolved compound 23-1 (530mg) in methylene dichloride (5ml) adds and contains hydrogenchloride De diox (4mol/l, 2ml), at room temperature stirs 3 and a half hours.The concentrating under reduced pressure solvent adds methyl alcohol (3ml), diethyl ether (7ml), propylene oxide (7ml) in residue, the powder that leaching is separated out cleans with vinyl acetic monomer and diethyl ether, obtains the title product (182mg) of white solid.
MS(ESI)m/z：474[M+H]
1H-NMR(CD 3OD)δ(ppm)：0.91(3H、t、J＝6.4Hz)、1.29-1.44(6H、m)、1.45-1.52(2H、m)、1.73-1.82(2H、m)、1.92-2.10(2H、m)、2.12-2.20(1H、m)、2.21-2.26(1H、m)、2.60-2.79(2H、m)、3.99(2H、d、J＝5.6Hz)、4.05(2H、t、J＝6.2Hz)、4.68(1H、t、J＝5.4Hz)、4.79-4.81(1H、m)、7.07(1H、d、J＝8.3Hz)、7.41-7.44(2H、m)。
Embodiment 24
2-amino-2-[2-(4-heptyl sulfo--3-trifluoromethyl) ethyl] propane-1, the 3-diol hydrochloride
(24-1) synthetic (the compound 24-1) of [1, two (methylol)-3-(the 4-heptyl sulfo--3-trifluoromethyl) propyl group of 1-] carboxylamine tertiary butyl ester
In methylene dichloride (30ml) solution of compound 1-1 (1.00g), ice-cold triethylamine (0.503ml), the Trifluoromethanesulfonic anhydride (0.607ml) of adding down directly stirred 1 hour down ice-cold.Add entry in the reaction solution, behind dichloromethane extraction, in water, saturated aqueous common salt, clean, use anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated.The residue that obtains is with silica gel column chromatography (hexane: vinyl acetic monomer=1: 2～1: 4) make with extra care, obtain the colorless oil of phenolic hydroxyl group by fluoroform sulphonate (triflate, ト リ Off ラ one ト) compound (500mg) protection, the acetonide deprotection.In this colorless oil De diox (10ml) solution, add diisopropylamine (0.377ml), heptanthiol (0.204ml), 4; Two (diphenylphosphino)-9 of 5-; 9-dimethyl-oxa-anthracene (Xantphos) (31mg), three (dibenzalacetone) palladium (0)-chloroform affixture (27mg), stirred 4 hours down at 120 ℃.In reaction solution, add entry, behind ethyl acetate extraction, clean with saturated aqueous common salt, use anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated.The residue that obtains is with silica gel column chromatography (hexane: vinyl acetic monomer=1: 2～1: 3) make with extra care, obtain the title product (390mg) of faint yellow oily thing.
1H-NMR(CDCl 3)δ(ppm)：0.88(3H、t、J＝6.8Hz)、1.23-1.38(6H、m)、1.39-1.50(2H、m)、1.46(9H、s)、1.60-1.68(2H、m)、1.86-1.91(2H、m)、2.61-2.66(2H、m)、2.92(2H、t、J＝7.4Hz)、3.20(2H、brs)、3.63-3.68(2H、m)、3.85-3.90(2H、m)、5.05(1H、brs)、7.25-7.30(1H、m)、7.39(1H、d、J＝8.0Hz)、7.45(1H、brs)。
(24-2) 2-amino-2-[2-(4-heptyl sulfo--3-trifluoromethyl) ethyl] propane-1, synthetic (the compound 24-2) of 3-diol hydrochloride
Dissolved compound 24-1 (390mg) in methylene dichloride (5ml) adds and contains hydrogenchloride De diox (4mol/l, 5ml), at room temperature stirs 4 hours.Concentration of reaction solution, residue cleans with diethyl ether, obtains white powder.Behind refining this white powder of preparation HPLC, add the ether (1mol/l, 15ml) that contains hydrogenchloride in the residue that obtains, process hydrochloride after, the leaching precipitate, drying obtains the title product (200mg) of white powder.
MS(ESI)m/z：394[M+H]
1H-NMR(DMSO-d 6)δ(ppm)：0.84(3H、t、J＝6.8Hz)、1.19-1.31(6H、m)、1.32-1.42(2H、m)、1.51-1.60(2H、m)、1.75-1.80(2H、m)、2.63-2.68(2H、m)、3.02(2H、t、J＝7.2Hz)、3.52(4H、d、J＝4.0Hz)、5.36(2H、brs)、7.47(1H、d、J＝8.4Hz)、7.56-7.59(2H、m)、7.74(3H、brs)。
Embodiment 25
2-amino-2-[2-(the hot sulfenyl of 4--3-trifluoromethyl) ethyl] propane-1, the 3-diol hydrochloride
(25-1) synthetic (the compound 25-1) of { 2,2-dimethyl--5-[2-(the hot sulfenyl of 4--3-trifluoromethyl) ethyl]-1,3-diox-5-yl } carboxylamine tertiary butyl ester
In methylene dichloride (30ml) solution of compound 1-1 (1.00g), add pyridine (0.926ml), ice-cold down, drip methylene dichloride (5ml) solution of Trifluoromethanesulfonic anhydride (0.480ml), directly stirred 2 and a half hours down ice-cold.In reaction solution, add saturated sodium bicarbonate aqueous solution, behind dichloromethane extraction, clean with saturated aqueous common salt, use anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated.The residue that obtains is with silica gel column chromatography (hexane: vinyl acetic monomer=3: 1～2: 1) make with extra care, obtain compound (970mg) white solid of phenolic hydroxyl group by the fluoroform sulphonate protection.In this white solid De diox (20ml) solution, add Diisopropylamine (0.631ml), spicy thioalcohol (0.375ml), 4; Two (diphenylphosphino)-9 of 5-; 9-dimethyl-oxa-anthracene (Xantphos) (53mg), three (dibenzalacetone) palladium (0)-chloroform affixture (46mg), stirred 2 days down at 120 ℃.And then; In reaction soln, add Diisopropylamine (0.631ml), spicy thioalcohol (0.375ml), 4; Two (diphenylphosphino)-9 of 5-, 9-dimethyl-oxa-anthracene (Xantphos) are (53mg), three (dibenzalacetone) palladium (0)-chloroform pays and add thing (46mg), stir 1 day down at 120 ℃.In reaction solution, add entry, behind ethyl acetate extraction, clean with saturated aqueous common salt, use anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated.The residue that obtains is with silica gel column chromatography (hexane: vinyl acetic monomer=5: 1～2: 1) make with extra care, obtain the title product (910mg) of faint yellow solid.
1H-NMR(CDCl 3)δ(ppm)：0.88(3H、t、J＝6.8Hz)、1.24-1.36(8H、m)、1.42-1.50(2H、m)、1.43(3H、s)、1.44(3H、s)、1.47(9H、s)、1.60-1.70(2H、m)、1.96-2.00(2H、m)、2.55-2.60(2H、m)、2.91(2H、t、J＝7.4Hz)、3.69(2H、d、J＝11.7Hz)、3.89(2H、d、J＝11.7Hz)、4.98(1H、brs)、7.25-7.29(1H、m)、7.38(1H、d、J＝8.2Hz)、7.44(1H、d、J＝1.0Hz)。
(25-2) 2-amino-2-[2-(the hot sulfenyl of 4--3-trifluoromethyl) ethyl] propane-1, synthetic (the compound 25-2) of 3-diol hydrochloride
Dissolved compound 25-1 (910mg) in ethanol (20ml) adds concentrated hydrochloric acid (2ml), in 80 ℃, stirs 2 hours.Concentration of reaction solution, residue cleans with diethyl ether, obtains the title product (630mg) of white powder.
MS(ESI)m/z：408[M+H]
1H-NMR(DMSO-d 6)δ(ppm)：0.85(3H、t、J＝6.8Hz)、1.19-1.32(8H、m)、1.33-1.43(2H、m)、1.51-1.60(2H、m)、1.76-1.81(2H、m)、2.64-2.69(2H、m)、3.02(2H、t、J＝7.2Hz)、3.52(4H、d、J＝4.8Hz)、5.38(2H、t、J＝5.0Hz)、7.47(1H、d、J＝8.3Hz)、7.56-7.59(2H、m)、7.83(3H、brs)。
Embodiment 26
2-amino-4-(the hot sulfenyl of 4--3-trifluoromethyl)-2-(phosphinylidyne oxygen ylmethyl) butanols
(26-1) synthetic (the compound 26-1) of [1-methylol-3-(the hot sulfenyl of 4--3-trifluoromethyl)-1-(methoxymethoxy) methyl] propyl carbamic acid tertiary butyl ester
Dissolved compound 25-2 (560mg) in methyl alcohol (10ml) adds triethylamine (0.531ml) and di-tert-butyl dicarbonic acid ester (412mg), at room temperature stirs 12 hours.And then in reaction solution, add di-tert-butyl dicarbonic acid ester (300mg), at room temperature stirred 12 hours.Add entry, behind ethyl acetate extraction, organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated, and obtains flaxen oily matter.In methylene dichloride (20ml) solution of this oily matter, the ice-cold N that adds down, N-diisopropylethylamine (0.285ml) and methoxymethyl muriate (0.121ml), ice-cold stirring down 10 minutes was at room temperature stirred 14 hours again.In reaction solution, add entry, behind dichloromethane extraction, organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains is refining with silica gel chromatography, obtains title product (290mg) and [1, two (the methylol)-3-of 1-(the hot sulfenyl of 4--3-trifluoromethyl)] propyl carbamic acid tertiary butyl ester (280mg) as colorless oil respectively.In [1 of above-mentioned recovery; Two (the methylol)-3-of 1-(the hot sulfenyl of 4--3-trifluoromethyl)] in methylene dichloride (15ml) solution of propyl carbamic acid tertiary butyl ester; The ice-cold N that adds down; N-diisopropylethylamine (0.129ml) and methoxymethyl muriate (0.063ml), ice-cold stirring down 5 minutes was at room temperature stirred 14 hours again.In reaction solution, add entry, behind dichloromethane extraction, organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains is refining with silica gel chromatography, obtains the title product (210mg) of colorless oil.Merge with the title product that obtains in the first set reaction, the total amount of title product is 500mg.
1H-NMR(CDCl 3)δ(ppm)：0.87(3H、t、J＝6.8Hz)、1.25-1.38(8H、m)、1.39-1.49(2H、m)、1.45(9H、s)、1.59-1.70(2H、m)、1.85-1.93(1H、m)、2.04-2.12(1H、m)、2.54-2.64(1H、m)、2.66-2.76(1H、m)、2.91(2H、t、7.4Hz)、3.39(3H、s)、3.51(1H、d、J＝9.6Hz)、3.70-3.79(3H、m)、3.94(1H、brs)、4.65(2H、s)、5.17(1H、brs)、7.27-7.30(1H、m)、7.39(1H、d、J＝8.1Hz)、7.45(1H、d、J＝1.3Hz)。
(26-2) synthetic (the compound 26-2) of [1-solutions of dimethyl phosphoryl oxygen ylmethyl-3-(the hot sulfenyl of 4--3-trifluoromethyl)-1-(methoxymethoxy) methyl-propyl] carboxylamine tertiary butyl ester
In methylene dichloride (3ml) solution of compound 26-1 (500mg), add pyridine (2ml), carbon tetrabromide (334mg) and trimethyl phosphite (0.161ml), at room temperature stirred 4 and a half hours.And then, in reaction solution, add trimethyl phosphite (0.080ml), at room temperature stirred 2 and a half hours.In reaction solution, add entry, behind chloroform extraction, organic layer cleans in water, saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains is with silica gel column chromatography (hexane: vinyl acetic monomer=1: 3～1: 4) make with extra care, obtain the title product (490mg) of brown oil.
1H-NMR(CD 3OD)δ(ppm)：0.89(3H、t、J＝6.7Hz)、1.26-1.38(8H、m)、1.39-1.51(2H、m)、1.45(9H、s)、1.55-1.68(2H、m)、1.88-1.97(1H、m)、2.05-2.16(1H、m)、2.68(2H、t、J＝8.5Hz)、2.96(2H、t、J＝7.3Hz)、3.60(1H、d、J＝9.7Hz)、3.69(1H、d、J＝9.7Hz)、3.77(3H、s)、3.80(3H、s)、4.14-4.18(1H、m)、4.30-4.34(1H、m)、4.64(2H、s)、7.37-7.39(1H、m)、7.49-7.52(2H、m)。
(26-3) synthetic (the compound 26-3) of 2-amino-4-(the hot sulfenyl of 4--3-trifluoromethyl)-2-(phosphinylidyne oxygen ylmethyl) butanols
Dissolved compound 26-2 (490mg) in ethanol (5ml) adds concentrated hydrochloric acid (1ml), stirs 2 hours down at 50 ℃.The concentrating under reduced pressure solvent at the ice-cold iodate trimethyl silyl (0.527ml) that adds down, stirred 1 hour down ice-cold in methylene dichloride (7ml) solution of residue.The solvent concentrating under reduced pressure adds acetonitrile (15ml) to half the.The powder that leaching is separated out cleans with acetonitrile and diethyl ether, obtains the title product (245mg) of faint yellow solid.
MS(ESI)m/z：488[M+H]
1H-NMR(CD 3OD)δ(ppm)：0.89(3H、t、J＝6.8Hz)、1.24-1.38(8H、m)、1.39-1.50(2H、m)、1.56-1.68(2H、m)、1.95-2.01(2H、m)、2.68-2.80(2H、m)、2.97(2H、t、J＝7.3Hz)、3.71(2H、brs)、3.98-4.04(2H、m)、7.46(1H、d、J＝8.0Hz)、7.53(1H、d、J＝8.2Hz)、7.57(1H、brs)。
Embodiment 27
2-amino-2-[2-(4-hexyl sulfo--3-trifluoromethyl) ethyl] propane-1, the 3-diol hydrochloride
(27-1) synthetic (the compound 27-1) of { 2,2-dimethyl--5-[2-(the own sulfenyl of 4--3-trifluoromethyl) ethyl]-1,3-diox-5-yl } carboxylamine tertiary butyl ester
In methylene dichloride (30ml) solution of compound 1-1 (1.00g), add pyridine (0.926ml),, directly stirred 2 and a half hours down ice-cold at ice-cold methylene dichloride (5ml) solution that drips Trifluoromethanesulfonic anhydride (0.480ml) down.In reaction solution, add saturated sodium bicarbonate aqueous solution, behind dichloromethane extraction, clean with saturated aqueous common salt, use anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated.The residue that obtains is with silica gel column chromatography (hexane: vinyl acetic monomer=3: 1～2: 1) make with extra care, obtain compound (980mg) white solid of phenolic hydroxyl group by the trifluoro-methanyl sulfonate protection.In this white solid De diox (20ml) solution; Add Diisopropylamine (0.638ml), hexylmercaptan (0.301ml), 4; Two (diphenylphosphino)-9 of 5-; 9-dimethyl-oxa-anthracene (Xantphos) (53mg), three (dibenzalacetone) palladium (0)-chloroform affixture (46mg), stirred 2 days down at 120 ℃.And then in reaction soln, add Diisopropylamine (0.631ml), spicy thioalcohol (0.375ml), 4; Two (diphenylphosphino)-9 of 5-; 9-dimethyl-oxa-anthracene (Xantphos) (53mg), three (dibenzalacetone) palladium (0)-chloroform pays and add thing (46mg), stirs 1 day down at 120 ℃.In reaction solution, add entry, behind ethyl acetate extraction, clean with saturated aqueous common salt, use anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated.The residue that obtains is with silica gel column chromatography (hexane: vinyl acetic monomer=5: 1～3: 1) make with extra care, obtain { 2,2-dimethyl--5-[2-(the own sulfenyl of 4--3-trifluoromethyl) ethyl]-1,3-diox-5-yl } carboxylamine tertiary butyl ester of faint yellow solid.The faint yellow solid of above-mentioned acquisition is dissolved in the ethanol (15ml), adds concentrated hydrochloric acid (1.5ml), stirs 2 hours down at 80 ℃.Concentration of reaction solution, residue cleans with diethyl ether, obtains white solid.This white solid is refining with preparation HPLC, adds the ether (1mol/l, 15ml) that contains hydrogenchloride in the residue that obtains, process hydrochloride after, the leaching precipitate, drying obtains the title product (132mg) of white powder.
MS(ESI)m/z：380[M+H]
1H-NMR(DMSO-d 6)δ(ppm)：0.85(3H、t、J＝6.6Hz)、1.20-1.31(4H、m)、1.32-1.43(2H、m)、1.51-1.60(2H、m)、1.75-1.81(2H、m)、2.63-2.69(2H、m)、3.03(2H、t、J＝7.2Hz)、3.52(4H、d、J＝5.0Hz)、5.41(2H、t、J＝5.1Hz)、7.47(1H、d、J＝8.7Hz)、7.57-7.59(2H、m)、7.84(3H、brs)。
Embodiment 28
(E)-and 2-amino-2-[2-(4-oxygen in heptan base-3-trifluoromethyl) vinyl] propane-1, the 3-glycol
(28-1) synthetic (the compound 28-1) of 4-oxygen in heptan base-3-trifluoromethyl TRIMETHOXY BENZOIC ACID (FOR MANUFACTURING OF T.M.
At the N of tert.-butoxy potassium (20.7g), add n-Heptyl alcohol (15.6mL) in dinethylformamide (120mL) suspension liquid, stirred at room temperature 30 minutes.0 ℃ of N that drips 4-fluoro-3-trifluoromethyl TRIMETHOXY BENZOIC ACID (FOR MANUFACTURING OF T.M. (16.7g) down in reaction solution, dinethylformamide (60mL) solution stirred one hour down at 70 ℃.Behind the ice-cold reaction solution, add entry (320mL), at room temperature add 6M-hydrochloric acid (40mL).At room temperature stirred the crystallization that leaching is separated out 30 minutes.This crystallization is dissolved under 70 ℃ in the ethanol (60mL), under uniform temp, drips water (96mL), stirs 30 minutes.After placing cool to room temperature, stirred 30 minutes down ice-cold, the crystallization that leaching is separated out obtains Sandy crystalline title product (24.1g).
1H-NMR(CDCl 3)δ(ppm)：0.90(3H、t、J＝6.6Hz)、1.28-1.49(8H、m)、1.80-1.90(2H、m)、4.13(2H、t、J＝6.3Hz)、7.04(1H、d、J＝8.7Hz)、8.24(1H、dd、J＝2.1Hz、9.0Hz)、8.33(1H、d、J＝1.8Hz)。
(28-2) synthetic (the compound 28-2) of 4-oxygen in heptan base-3-trifluoromethyl benzyl alcohol
N at compound 28-1 (30.0g); In dinethylformamide (240mL) solution; Under under the nitrogen atmosphere gas 0 ℃; Drip two (2-methoxy ethoxy) alanate/toluene solution (65wt%) toluene (80mL) solution (20.0g), drip two (2-methoxy ethoxy) alanate/toluene solution (65wt%) toluene (80mL) solution (80.0g) again.After at room temperature stirring 2 hours, ice-cold reaction solution, Dropwise 5 N-aqueous sodium hydroxide solution (200mL) at room temperature stirred 30 minutes.Separatory extraction organic layer cleans with 5N-aqueous sodium hydroxide solution (100mL), uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated, and obtains the title product (28.3g) of white crystals.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.6Hz)、1.26-1.56(8H、m)、1.65(1H、t、J＝5.7Hz)、1.77-1.85(2H、m)、4.04(2H、t、J＝6.3Hz)、4.65(2H、d、J＝5.7Hz)、6.97(1H、d、J＝8.4Hz)、7.47(1H、dd、J＝1.5Hz、8.4Hz)、7.57(1H、d、J＝1.8Hz)。
(28-3) synthetic (the compound 28-3) of 4-oxygen in heptan base-3-trifluoromethyl benzyl chloride thing
In methylene dichloride (107mL) solution of compound 28-2 (26.8g), add several N, dinethylformamide is in 0 ℃ of following thionyl chloride (8.09mL).Under uniform temp, stirred 2 hours, in reaction solution, add entry (50mL).Separatory extraction organic layer, water (50mL), saturated sodium bicarbonate water (70mL) clean, and use anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and is desolvated, and obtains the title product (28.3g) of white crystals.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.5Hz)、1.26-1.54(8H、m)、1.77-1.86(2H、m)、4.04(2H、t、J＝6.4Hz)、4.56(2H、s)、6.96(1H、d、J＝8.6Hz)、7.49(1H、dd、J＝2.0Hz、8.5Hz)、7.58(1H、d、J＝1.9Hz)。
(28-4) synthetic (the compound 28-4) of (4-oxygen in heptan base-3-trifluoromethyl benzyl) diethyl phosphonate
The triethyl-phosphite (29.3 of reflux compound 28-3 (27.3g) under nitrogen atmosphere gas
G) solution is 4 hours.Heat up in a steamer triethyl-phosphite through decompression, obtain the title product (36.1g) of faint yellow oily thing.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.6Hz)、1.23-1.54(14H、m)、1.77-1.86(2H、m)、3.10(2H、d、J＝21.3Hz)、3.98-4.08(4H、m)、6.93(1H、d、J＝8.4Hz)、7.42(1H、dd、J＝2.4Hz、8.4Hz)、7.45(1H、d、J＝2.1Hz)。
Synthetic (the compound 28-5) of (28-5) (E)-{ 2,2-dimethyl--5-[2-(4-oxygen in heptan base-3-trifluoromethyl) vinyl]-1,3-diox-5-yl } carboxylamine tertiary butyl ester
In THF (177mL) solution of tert.-butoxy potassium (24.9g), ice-cold THF (203mL) solution that drips compound 28-4 (35.1g) and reference example compound 1-2 (28.8g) down stirred 5 hours down at 0 ℃.In reaction solution, add heptane (203mL), then add entry (203mL), separatory extraction organic layer, water cleans, and uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and is desolvated.Residue with hexane (50mL) outstanding turbid after, leaching obtains the title product (32.6g) of white crystals.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.6Hz)、1.30-1.57(8H、m)、1.44(9H、s)、1.47(3H、s)、1.49(3H、s)、1.76-1.84(2H、m)、3.90(2H、d、J＝11.4Hz)、3.94(2H、d、J＝13.8Hz)、4.03(2H、t、J＝6.3Hz)、5.21(1H、brs)、6.10(1H、d、J＝16.5Hz)、6.48(1H、d、J＝16.5Hz)、6.91(1H、d、J＝8.4Hz)、7.43-7.46(1H、m)、7.55(1H、d、J＝1.8Hz)。
(28-6) (E)-2-amino-2-[2-(4-oxygen in heptan base-3-trifluoromethyl) vinyl] propane-1, synthetic (the compound 28-6) of 3-diol hydrochloride
In ethanol (15ml), among the dissolved compound 28-5 (500mg), add concentrated hydrochloric acid (1.5ml), stirred 1 and a half hours down at 80 ℃.Concentration of reaction solution, residue cleans with diethyl ether, obtains the title product (330mg) of white powder.
MS(ESI)m/z：359
1H-NMR(DMSO-d 6)δ(ppm)：0.86(3H、t、J＝6.8Hz)、1.25-1.39(6H、m)、1.40-1.46(2H、m)、1.69-1.77(2H、m)、3.59-3.67(4H、m)、4.11(2H、t、J＝6.2Hz)、5.48(2H、t、J＝5.3Hz)、6.24(1H、d、J＝16.8Hz)、6.71(1H、d、J＝16.8Hz)、7.27(1H、d、J＝9.3Hz)、7.25-7.28(2H、m)、8.12(3H、brs)。
Embodiment 29
(E)-2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-(phosphinylidyne oxygen ylmethyl)-3-butene-1-alcohol
Synthetic (the compound 29-1) of (29-1) (E)-{ 4-two (tertiary butyl) phosphinylidyne oxygen ylmethyl-2-methyl-4-[2-(4-oxygen in heptan base-3-trifluoromethyl) vinyl]-2-oxazoline }
At the N of compound 28-6 (280mg), add N in dinethylformamide (10ml) solution, N-diisopropylethylamine (0.366ml), original trimethyl acetate (0.129ml) stirred 5 hours down at 120 ℃.In reaction solution, add entry, behind ethyl acetate extraction, in water, saturated aqueous common salt, clean, use anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated, and obtains the 270mg brown oil.In the solution of the methylene dichloride (5ml) of this brown oil (270mg) and acetonitrile (2ml), add 1H-tetrazolium (95mg), di-t-butyl diethylammonium phosphoramidite (0.407ml), at room temperature stirred 2 hours.Ice-cold reaction soln adds the decane solution (5-6M, 0.408ml) that contains tert-butyl hydroperoxide, at room temperature stirs 30 minutes.In reaction solution, add saturated sodium bicarbonate aqueous solution, behind chloroform extraction, organic layer is used anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains with silica gel column chromatography (hexane: vinyl acetic monomer=1: 3～have only vinyl acetic monomer) refining, obtain the title product (200mg) of yellow oil.
1H-NMR(CD 3OD)δ(ppm)：0.90(3H、t、J＝6.9Hz)、1.29-1.45(6H、m)、1.47-1.53(2H、m)、1.49(9H、s)、1.50(9H、s)、1.75-1.83(2H、m)、2.05(3H、s)、3.94-3.98(1H、m)、4.00-4.05(1H、m)、4.08(2H、t、J＝6.2Hz)、4.23(1H、d、J＝8.7Hz)、4.50(1H、d、J＝8.7Hz)、6.30(1H、d、J＝16.2Hz)、6.64(1H、d、J＝16.2Hz)、7.11(1H、d、J＝8.4Hz)、7.59-7.62(2H、m)。
(29-2) E-[2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-(phosphinylidyne oxygen ylmethyl)-3-butene-1-alcohol] (compound 29-2)
Dissolved compound 29-1 (200mg) in ethanol (5ml) adds concentrated hydrochloric acid (1ml), stirs 3 hours down at 50 ℃.The concentrating under reduced pressure solvent adds methyl alcohol (3ml), diethyl ether (3ml), propylene oxide (5ml) in residue, the powder that leaching is separated out cleans with vinyl acetic monomer and diethyl ether, obtains the title product (45mg) of white solid.
MS(ESI)m/z：456[M+H]
1H-NMR(CD 3OD)δ(ppm)：0.91(3H、t、J＝6.9Hz)、1.27-1.47(6H、m)、1.45-1.54(2H、m)、1.76-1.83(2H、m)、3.75(1H、d、J＝11.6Hz)、3.83(1H、d、J＝11.6Hz)、3.98-4.04(1H、m)、4.07-4.15(1H、m)、4.09(2H、t、J＝6.3Hz)、6.22(1H、d、J＝16.7Hz)、6.76(1H、d、J＝16.7Hz)、7.14(1H、d、J＝9.3Hz)、7.65-7.67(2H、m)。
Embodiment 30
2-amino-2-[2-(3-difluoromethyl-4-oxygen in heptan base phenyl) ethyl] propane-1, the 3-diol hydrochloride
(30-1) synthetic (the compound 30-1) of 2-benzyloxy-5-bromobenzene formaldehyde
At the N of 5-bromo salicylic aldehyde (25.0g) and salt of wormwood (51.4g), the ice-cold cylite (15.4ml) that adds down in dinethylformamide (250ml) suspension liquid ice-coldly stirred 40 minutes down, again stirring at room 15 hours.In water, add reaction solution, behind ethyl acetate extraction,, use anhydrous magnesium sulfate drying with the 0.1M aqueous sodium hydroxide solution, then with the saturated aqueous common salt cleaning.Decompression is heated up in a steamer and is desolvated, and the residue that obtains is outstanding turbid behind hexane (200ml), and leaching obtains the title product (32.7g) of micro-yellow powder.
1H-NMR(CDCl 3)δ(ppm)：5.19(2H、s)、6.95(1H、d、J＝8.8Hz)、7.34-7.43(5H、m)、7.61(1H、dd、J＝2.8、8.8Hz)、7.95(1H、d、J＝2.8Hz)、10.46(1H、s)。
(30-2) synthetic (the compound 30-2) of 1-benzyloxy-4-bromo-2-benzal fluoride
In methylene dichloride (5ml) solution of compound 30-1 (2.70g), add methylene dichloride (5ml) solution of three fluoro diethylamino sulphur (DAST, 1.66g), at room temperature stirred 21 hours.In water, add reaction solution, behind dichloromethane extraction, organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying.Decompression is heated up in a steamer and is desolvated, and the residue that obtains is refining with silica gel chromatography, obtains the title product (2.16g) of colorless oil.
1H-NMR(CDCl 3)δ(ppm)：5.11(2H、s)、6.86(1H、d、J＝9.1Hz)、6.95(1H、t、J＝55.3Hz)、7.33-7.42(5H、m)、7.49(1H、dd、J＝1.6、9.8Hz)、7.69(1H、d、J＝1.9Hz)。
(30-3) synthetic (the compound 30-3) of { 5-[(4-benzyloxy-3-difluoromethyl phenyl) ethynyl]-2,2-dimethyl--1,3-diox-5-yl } carboxylamine tertiary butyl ester
In acetonitrile (200ml), add compound 30-2 (9.48g), with known method (for example tetradron the 57th rolls up (calendar year 2001) 6531-6538 page or leaf) synthetic (2; 2-dimethyl--5-ethynyl-1; 3-diox-5-yl) carboxylamine tertiary butyl ester (7.34g), 2-dicyclohexyl phosphino--2 '; 4 ', 6 '-tri isopropyl biphenyl (868mg), two (acetonitrile) palladium (II) dichloride (157mg), cesium carbonate (25.6g) stirred 8 hours down at 80 ℃.In reaction solution, add entry, behind ethyl acetate extraction, clean with saturated aqueous common salt, use anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated.Residue is refining with silica gel column chromatography, obtains the title product (11.1g) of filbert oily thing.
1H-NMR(CDCl 3)δ(ppm)：1.45(3H、s)、1.48(9H、s)、1.50(3H、s)、4.03(2H、d、J＝11.2Hz)、4.10(2H、d、J＝11.2Hz)、5.13(2H、s)、5.20(1H、brs)、6.91(1H、d、J＝8.6Hz)、6.94(1H、t、J＝55.4Hz)、7.33-7.40(5H、m)、7.46(1H、d、J＝8.6Hz)、7.65(1H、s)。
(30-4) synthetic (the compound 30-4) of { 5-[2-(3-difluoromethyl-4-hydroxy phenyl) ethyl]-2,2-dimethyl--1,3-diox-5-yl } carboxylamine tertiary butyl ester
1, dissolved compound 30-3 (11.1g) in the 4-diox (250ml) adds 10% year palladium gac (3.5g), is stirring 3.5 hours under the atmosphere of hydrogen gas, under the room temperature.After in the nitrogen replacement reaction vessel, filtering solution, concentrated filtrate.Residue outstanding turbid in the mixing solutions of Di Iso Propyl Ether and hexane after, leaching obtains the title product (8.17g) of white powder.
1H-NMR(CDCl 3)δ(ppm)：1.43(3H、s)、1.44(3H、s)、1.48(9H、s)、1.92-1.96(2H、m)、2.50-2.54(2H、m)、3.69(2H、d、J＝11.7Hz)、3.89(2H、d、J＝11.7Hz)、5.03(1H、brs)、5.57(1H、brs)、6.77(1H、d、J＝8.4Hz)、6.84(1H、t、J＝55.5Hz)、7.12(1H、d、J＝8.4Hz)、7.23(1H、s)。
(30-5) 2-amino-2-[2-(3-difluoromethyl-4-oxygen in heptan base phenyl) ethyl] propane-1, synthetic (the compound 30-5) of 3-diol hydrochloride
At N, dissolved compound 30-4 (500mg) in the dinethylformamide (10ml) adds salt of wormwood (516mg), n-heptyl bromide (0.240ml), at room temperature stirs 15 hours.In reaction solution, add entry, behind ethyl acetate extraction, in water, saturated aqueous common salt, clean, use anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated, and obtains the 620mg colorless oil.This colorless oil of dissolving adds concentrated hydrochloric acid (1.5ml) in ethanol (15ml), stirs 1 hour down at 80 ℃.Concentration of reaction solution, residue cleans with diethyl ether, obtains white powder.This white powder is refining with preparation HPLC, in the residue that obtains, adds the ether (1mol/l, 15ml) that contains hydrogenchloride, process hydrochloride after, the leaching precipitate, drying obtains the title product (160mg) of white powder.
MS(ESI)m/z：360[M+H]
1H-NMR(DMSO-d 6)δ(ppm)：0.87(3H、t、J＝6.8Hz)、1.25-1.37(6H、m)、1.38-1.45(2H、m)、1.68-1.79(4H、m)、2.56-2.62(2H、m)、3.52(4H、d、J＝4.0Hz)、4.02(2H、t、J＝6.4Hz)、5.40(2H、t、J＝4.5Hz)、7.05(1H、t、J＝55.4Hz)、7.07(1H、d、J＝8.6Hz)、7.32(1H、d、J＝8.6Hz)、7.36(1H、s)、7.80(3H、brs)。
Embodiment 31
2-amino-4-(3-difluoromethyl-4-oxygen in heptan base phenyl)-2-(phosphinylidyne oxygen ylmethyl) butanols
(31-1) synthetic (the compound 31-1) of 4-two (tertiary butyl) phosphinylidyne oxygen ylmethyl-2-methyl-4-[2-(3-difluoromethyl-4-oxygen in heptan base phenyl) ethyl]-2-oxazoline
At the N of compound 30-5 (115mg), add N in dinethylformamide (5ml) solution, N-diisopropylethylamine (0.156ml), original trimethyl acetate (0.055ml) stirred 12 and a half hours in 120 ℃.In this reaction solution, add N again, N-diisopropylethylamine (0.156ml), original trimethyl acetate (0.055ml) stirred 3 and a half hours down at 120 ℃.In reaction solution, add entry, behind ethyl acetate extraction, in water, saturated aqueous common salt, clean, use anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated, and obtains the 140mg brown oil.In the solution of the methylene dichloride (3ml) of this brown oil (140mg) and acetonitrile (1ml), add 1H-tetrazolium (41mg), di-t-butyl diethylammonium phosphoramidite (0.174ml), at room temperature stirred 2 hours.Ice-cold reaction soln adds the decane solution (5-6M, 0.174ml) that contains tert-butyl hydroperoxide, at room temperature stirs 20 minutes.In reaction solution, add saturated sodium bicarbonate aqueous solution, behind chloroform extraction, organic layer is used anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains with silica gel column chromatography (hexane: vinyl acetic monomer=1: 4～have only vinyl acetic monomer) refining, obtain the title product (110mg) of yellow oil.
1H-NMR(CD 3OD)δ(ppm)：0.91(3H、t、J＝6.7Hz)、1.30-1.42(6H、m)、1.43-1.53(2H、m)、1.48(18H、2×s)、1.70-1.90(4H、m)、2.01(3H、s)、2.51-2.69(2H、m)、3.87-3.92(2H、m)、4.02(2H、t、J＝6.4Hz)、4.17(1H、d、J＝9.0Hz)、4.32(1H、d、J＝9.0Hz)、6.91(1H、t、J＝55.8Hz)、6.97(1H、d、J＝8.5Hz)、7.29(1H、d、J＝8.5Hz)、7.36(1H、s)。
(31-2) synthetic (the compound 31-2) of 2-amino-4-(3-difluoromethyl-4-oxygen in heptan base phenyl)-2-(phosphinylidyne oxygen ylmethyl) butanols
Dissolved compound 31-1 (110mg) in ethanol (5ml) adds concentrated hydrochloric acid (1ml), stirs 4 hours down at 50 ℃.The concentrating under reduced pressure solvent adds methyl alcohol (1ml), diethyl ether (1ml), propylene oxide (2ml) in residue, the powder that leaching is separated out cleans with vinyl acetic monomer and diethyl ether, obtains the title product (60mg) of faint yellow solid.
MS(ESI)m/z：440[M+H]
1H-NMR(CD 3OD)δ(ppm)：0.91(3H、t、J＝6.8Hz)、1.26-1.43(6H、m)、1.44-1.52(2H、m)、1.74-1.82(2H、m)、1.92-2.00(2H、m)、2.59-2.71(2H、m)、3.70(2H、brs)、3.91-4.04(4H、m)、6.92(1H、t、J＝55.8Hz)、6.98(1H、d、J＝8.5Hz)、7.33(1H、d、J＝8.3Hz)、7.40(1H、brs)。
Embodiment 32
2-amino-2-[2-(3-difluoromethyl-4-octyloxyphenyl) ethyl] propane-1, the 3-diol hydrochloride
(32-1) synthetic (the compound 32-1) of { 2,2-dimethyl--5-[2-(3-difluoromethyl-4-octyloxyphenyl) ethyl]-1,3-diox-5-yl } carboxylamine tertiary butyl ester
At N, dissolved compound 30-4 (600mg) in the dinethylformamide (10ml) adds salt of wormwood (412mg), 1-bromooctane (0.311ml), at room temperature stirs 2 hours.In reaction solution, add entry, behind ethyl acetate extraction, in water, saturated aqueous common salt, clean; Use anhydrous magnesium sulfate drying; Decompression is heated up in a steamer and is desolvated, and the residue that obtains is with silica gel column chromatography (hexane: vinyl acetic monomer=50: 1～3: 1) make with extra care, obtain the title product (230mg) of colorless oil.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.8Hz)、1.25-1.49(8H、m)、1.40-1.50(2H、m)、1.42(3H、s)、1.44(3H、s)、1.47(9H、s)、1.75-1.81(2H、m)、1.91-1.98(2H、m)、2.50-2.57(2H、m)、3.68(2H、d、J＝11.8Hz)、3.89(2H、d、J＝11.7Hz)、3.97(2H、t、J＝6.4Hz)、4.98(1H、brs)、6.82(1H、d、J＝8.4Hz)、6.93(1H、t、J＝55.8Hz)、7.21(1H、d、J＝8.0Hz)、7.35(1H、brs)。
(32-2) 2-amino-2-[2-(3-difluoromethyl-4-octyloxyphenyl) ethyl] propane-1, synthetic (the compound 32-2) of 3-diol hydrochloride
Dissolved compound 32-1 (230mg) in ethanol (10ml) adds concentrated hydrochloric acid (1ml), stirs 2 hours down at 80 ℃.Concentration of reaction solution, residue cleans with diethyl ether, obtains the title product (105mg) of white powder.
MS(ESI)m/z：374[M+H]
1H-NMR(DMSO-d 6)δ(ppm)：0.86(3H、t、J＝6.8Hz)、1.24-1.38(8H、m)、1.39-1.44(2H、m)、1.68-1.80(4H、m)、2.55-2.62(2H、m)、3.52(4H、d、J＝4.6Hz)、4.01(2H、t、J＝6.4Hz)、5.39(2H、brt、J＝4.8Hz)、7.05(1H、t、J＝55.4Hz)、7.07(1H、d、J＝8.5Hz)、7.32(1H、d、J＝8.5Hz)、7.36(1H、s)、7.79(3H、brs)。
Embodiment 33
2-amino-4-(3-difluoromethyl-4-octyloxyphenyl)-2-(phosphinylidyne oxygen ylmethyl) butanols
(33-1) synthetic (the compound 33-1) of 4-two (tertiary butyl) phosphinylidyne oxygen ylmethyl-2-methyl-4-[2-(3-difluoromethyl-4-octyloxyphenyl) ethyl]-2-oxazoline
At the N of compound 32-2 (226mg), add N in dinethylformamide (10ml) solution, N-diisopropylethylamine (0.296ml), original trimethyl acetate (0.139ml) stirred 2 and a half hours down at 120 ℃.In reaction solution, add entry, behind ethyl acetate extraction, in water, saturated aqueous common salt, clean, use anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated, and obtains the 220mg brown oil.In the solution of the methylene dichloride (5ml) of this brown oil (220mg) and acetonitrile (2ml), add 1H-tetrazolium (77mg), di-t-butyl diethylammonium phosphoramidite (0.329ml), at room temperature stirred 2 hours.Ice-cold reaction soln adds the decane solution (5-6M, 0.330ml) that contains tert-butyl hydroperoxide, at room temperature stirs 20 minutes.In reaction solution, add saturated sodium bicarbonate aqueous solution, behind chloroform extraction, organic layer is used anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains with silica gel column chromatography (hexane: vinyl acetic monomer=1: 4～have only vinyl acetic monomer) refining, obtain the title product (280mg) of yellow oil.
1H-NMR(CD 3OD)δ(ppm)：0.90(3H、t、J＝7.0Hz)、1.28-1.41(8H、m)、1.45-1.52(2H、m)、1.48(18H、2×s)、1.75-1.90(4H、m)、2.01(3H、s)、2.51-2.70(2H、m)、3.87-3.92(2H、m)、4.02(2H、t、J＝6.3Hz)、4.17(1H、d、J＝9.0Hz)、4.32(1H、d、J＝9.0Hz)、6.92(1H、t、J＝55.7Hz)、6.97(1H、d、J＝8.4Hz)、7.29(1H、d、J＝8.9Hz)、7.36(1H、brs)。
(33-2) synthetic (the compound 33-2) of 2-amino-4-(3-difluoromethyl-4-octyloxyphenyl)-2-(phosphinylidyne oxygen ylmethyl) butanols
Dissolved compound 33-1 (280mg) in ethanol (5ml) adds concentrated hydrochloric acid (1ml), stirs 3 and a half hours down at 50 ℃.The concentrating under reduced pressure solvent adds methyl alcohol (2ml), diethyl ether (2ml), propylene oxide (5ml) in residue, the powder that leaching is separated out cleans with methyl alcohol and diethyl ether, obtains the title product (175mg) of faint yellow solid.
MS(ESI)m/z：454[M+H]
1H-NMR(CD 3OD)δ(ppm)：0.90(3H、t、J＝6.9Hz)、1.26-1.42(8H、m)、1.44-1.52(2H、m)、1.75-1.82(2H、m)、1.92-1.99(2H、m)、2.62-2.72(2H、m)、3.67-3.74(2H、m)、3.94-4.04(4H、m)、6.92(1H、t、J＝55.8Hz)、6.98(1H、d、J＝8.5Hz)、7.33(1H、d、J＝8.5Hz)、7.40(1H、brs)。
Embodiment 34
2-amino-2-[2-(3-methyl fluoride-4-oxygen in heptan base phenyl) ethyl] propane-1, the 3-diol hydrochloride
(34-1) synthetic (the compound 34-1) of 5-bromo-2-oxygen in heptan benzaldehyde
At the N of 5-bromo salicylic aldehyde (5.00g) and salt of wormwood (10.3g), add bromo heptyl (4.10ml) in dinethylformamide (50ml) suspension liquid, at room temperature stirred 1.5 hours, stirred 5 hours down at 50 ℃ again.In water, add reaction solution, use ethyl acetate extraction.Organic layer is with the 1M aqueous sodium hydroxide solution, then with the saturated aqueous common salt cleaning, and behind anhydrous magnesium sulfate drying, decompression is heated up in a steamer and desolvated, and obtains the title product (7.61g) of yellow oil.
1H-NMR(CDCl 3)δ(ppm)：0.90(3H、t、J＝6.8Hz)、1.28-1.40(6H、m)、1.44-1.51(2H、m)、1.85(2H、quint、J＝7.0Hz)、4.06(2H、t、J＝6.5Hz)、6.88(1H、d、J＝8.9Hz)、7.60(1H、dd、J＝2.8、8.9Hz)、7.92(1H、d、J＝2.8Hz)、10.42(1H、s)。
(34-2) synthetic (the compound 34-2) of 5-bromo-2-oxy-benzyl in heptan alcohol
The ice-cold Peng Qinghuana (0.48g) that adds down stirred 1.5 hours down ice-cold in ethanol (80ml) solution of compound 34-1 (7.60g).In reaction solution, add 1M hydrochloric acid (50ml), ethanol is heated up in a steamer in decompression.Behind the residue dilute with water that obtains, use ethyl acetate extraction.Organic layer cleans with saturated aqueous common salt, and behind anhydrous magnesium sulfate drying, decompression is heated up in a steamer and desolvated, and obtains the title product (7.66g) of faint yellow oily thing.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.8Hz)、1.28-1.39(6H、m)、1.41-1.48(2H、m)、1.80(2H、quint、J＝7.0Hz)、2.26(1H、t、J＝6.3Hz)、3.98(2H、t、J＝6.5Hz)、4.65(2H、d、J＝5.9Hz)、6.74(1H、d、J＝8.6Hz)、7.34(1H、dd、J＝2.4、8.6Hz)、7.41(1H、d、J＝2.4Hz)。
(34-3) synthetic (the compound 34-3) of (5-bromo-2-oxy-benzyl in heptan) oxygen base-tertiary butyl dimethylsilane
At the N of compound 34-2 (7.66g), imidazoles (4.32g), add TERT-BUTYL DIMETHYL CHLORO SILANE (4.59g) in dinethylformamide (30ml) solution, stirred 14 hours.In reaction solution, add saturated sodium bicarbonate aqueous solution, use ethyl acetate extraction.Organic layer is with saturated sodium bicarbonate aqueous solution, then with the saturated aqueous common salt cleaning, and behind anhydrous magnesium sulfate drying, decompression is heated up in a steamer and desolvated, and obtains the title product (10.6g) of yellow oil.
1H-NMR(CDCl 3)δ(ppm)：0.12(6H、s)、0.89(3H、t、J＝6.8Hz)、0.96(9H、s)、1.28-1.38(6H、m)、1.40-1.47(2H、m)、1.77(2H、quint、J＝7.0Hz)、3.92(2H、t、J＝6.5Hz)、4.71(2H、s)、6.67(1H、d、J＝8.7Hz)、7.27(1H、dd、J＝2.4、8.7Hz)、7.55(1H、d、J＝2.4Hz)。
(34-4) synthetic (the compound 34-4) of { 5-[3-(t-butyldimethylsilyl oxygen ylmethyl)-4-oxygen in heptan base phenylacetylene base]-2,2-dimethyl--1,3-diox-5-yl } carboxylamine tertiary butyl ester
In acetonitrile (150ml), add compound 34-3 (10.5g), through known method (for example tetradron the 57th volume (calendar year 2001) 6531-6538 page or leaf) synthetic (2; 2-dimethyl--5-ethynyl-1; 3-diox-5-yl) carboxylamine tertiary butyl ester (6.46g), 2-dicyclohexyl phosphino--2 '; 4 ', 6 '-tri isopropyl biphenyl (725mg), two (acetonitrile) palladium (II) dichloride (131mg), cesium carbonate (21.4g) stirred 12 hours down at 80 ℃.In water, add reaction solution, behind ethyl acetate extraction, clean with saturated aqueous common salt, use anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated.Residue is refining with silica gel column chromatography, obtains the title product (11.7g) of brown oil.
1H-NMR(CDCl 3)δ(ppm)：0.11(6H、s)、0.89(3H、t、J＝6.8Hz)、0.95(9H、s)、1.28-1.38(6H、m)、1.40-1.47(2H、m)、1.45(3H、s)、1.48(9H、s)、1.50(3H、s)、1.77(2H、quint、J＝6.9Hz)、3.95(2H、t、J＝6.4Hz)、4.03(2H、d、J＝11.5Hz)、4.09(2H、d、J＝11.5Hz)、4.69(2H、s)、5.19(1H、brs)、6.71(1H、d、J＝8.5Hz)、7.27(1H、dd、J＝1.9、8.5Hz)、7.49(1H、s)。
(34-5) synthetic (the compound 34-5) of { 2,2-dimethyl--5-[2-(4-oxygen in heptan base-3-hydroxymethyl phenyl) ethyl]-1,3-diox-5-yl } carboxylamine tertiary butyl ester
1, dissolved compound 34-4 (11.7g) in the 4-diox (150ml) adds 1
0% year palladium gac (12.0g) was stirring 16 hours under the atmosphere of hydrogen gas, under the room temperature.After in the nitrogen replacement reaction vessel, filtering solution, concentrated filtrate.In THF (100ml) solution of the residue that obtains, the ice-cold 1M tetrahydrofuran solution (20ml) that adds the TBuA fluorochemical down, ice-cold stirring down 1.5 hours.Append the 1M tetrahydrofuran solution (10ml) of TBuA fluorochemical, stirred 4 hours down ice-cold again.In water, add reaction solution, behind ethyl acetate extraction, water, and saturated aqueous common salt clean, use anhydrous sodium sulfate drying, reduce pressure to heat up in a steamer and desolvate.Residue is refining with silica gel column chromatography, obtains the title product (5.99g) of filbert oily thing.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.8Hz)、1.28-1.39(6H、m)、1.42-1.47(2H、m)、1.42(3H、s)、1.43(3H、s)、1.47(9H、s)、1.79(2H、quint、J＝7.0Hz)、1.92-1.96(2H、m)、2.40(1H、t、J＝6.5Hz)、2.48-2.53(2H、m)、3.67(2H、d、J＝11.7Hz)、3.89(2H、d、J＝11.7Hz)、3.98(2H、t、J＝6.5Hz)、4.65(2H、d、J＝6.8Hz)、4.97(1H、brs)、6.77(1H、d、J＝8.0Hz)、7.04-7.07(2H、m)。
(34-6) synthetic (the compound 34-6) of { 2,2-dimethyl--5-[2-(3-methyl fluoride-4-oxygen in heptan base phenyl) ethyl]-1,3-diox-5-yl } carboxylamine tertiary butyl ester
The mixture of the 1M tetrahydrofuran solution (46.8ml) of compound 34-5 (3.74g), p-toluenesulfonyl fluorine (4.08g), molecular sieve 4A (3.74g) and TBuA fluorochemical refluxed stirred 12 hours down.In reaction solution, add ferrite, filter.In filtrating, add vinyl acetic monomer (200ml) and water (200ml), filter with ferrite.The organic layer of filtrating cleans with saturated aqueous common salt, uses anhydrous sodium sulfate drying, and decompression is heated up in a steamer and desolvated.Residue is refining with silica gel column chromatography, obtains the title product (0.92g) of colorless oil.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.7Hz)、1.26-1.38(6H、m)、1.40-1.47(2H、m)、1.42(3H、s)、1.43(3H、s)、1.47(9H、s)、1.77(2H、quint、J＝6.9Hz)、1.93-1.97(2H、m)、2.50-2.54(2H、m)、3.68(2H、d、J＝11.7Hz)、3.88(2H、d、J＝11.7Hz)、3.95(2H、t、J＝6.4Hz)、4.98(1H、brs)、5.42(2H、d、J＝47.9Hz)、6.78(1H、d、J＝8.5Hz)、7.11(1H、d、J＝8.5Hz)、7.17(1H、m)。
(34-7) 2-amino-2-[2-(3-methyl fluoride-4-oxygen in heptan base phenyl) ethyl] propane-1, synthetic (the compound 34-7) of 3-diol hydrochloride
Dissolved compound 34-6 (0.92g) in methyl alcohol (30ml) adds tosic acid (15mg), at room temperature stirs 3 hours.In reaction solution, add saturated sodium bicarbonate aqueous solution (10ml) and saturated aqueous common salt (100ml), behind ethyl acetate extraction, clean with saturated aqueous common salt, use anhydrous sodium sulfate drying, decompression is heated up in a steamer and is desolvated.The ice-cold 4M vinyl acetic monomer solution (1ml) that adds vinyl acetic monomer (1ml) and hydrogenchloride down in the residue that obtains, ice-cold stirring down 30 minutes.The solid that leaching is separated out cleans with Di Iso Propyl Ether, obtains the title product (44.4mg) of white powder.
MS(ESI)m/z：342[M+H]
1H-NMR(DMSO-d 6)δ(ppm)：0.87(3H、t、J＝6.7Hz)、1.26-1.36(6H、m)、1.37-1.44(2H、m)、1.71(2H、quint、J＝6.9Hz)、1.74-1.79(2H、m)、2.53-2.57(2H、m)、3.52(4H、d、J＝5.2Hz)、3.97(2H、t、J＝6.3Hz)、5.38(2H、d、J＝48.0Hz)、5.40(2H、t、J＝5.1Hz)、6.97(1H、d、J＝8.3Hz)、7.17-7.20(2H、m)、7.85(3H、brs)。
Embodiment 35
2-amino-2-[2-(3-methyl fluoride-4-oxygen in heptan base phenyl) ethyl] propane-1, the 3-diol hydrochloride
(35-1) synthetic (the compound 35-1) of 5-bromo-2-octyloxy phenyl aldehyde
At the N of 5-bromo salicylic aldehyde (5.00g) and salt of wormwood (10.3g), add bromo octyl group (4.52ml) in dinethylformamide (50ml) suspension liquid, at room temperature stirred 1.5 hours, stirred 3.5 hours down at 50 ℃ again.In water, add reaction solution, use ethyl acetate extraction.Organic layer cleans 3 times with saturated aqueous common salt, and behind anhydrous magnesium sulfate drying, decompression is heated up in a steamer and desolvated, and obtains the title product (7.72g) of white solid.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.3Hz)、1.25-1.38(8H、m)、1.44-1.51(2H、m)、1.84(2H、quint、J＝6.8Hz)、4.06(2H、t、J＝6.4Hz)、6.88(1H、d、J＝8.9Hz)、7.61(1H、d、J＝8.9Hz)、7.92(1H、s)、10.42(1H、s)。
(35-2) synthetic (the compound 35-2) of 5-bromo-2-octyloxy benzyl alcohol
The ice-cold Peng Qinghuana (0.47g) that adds down stirred 30 minutes down ice-cold in ethanol (80ml) solution of compound 35-1 (7.72g).In reaction solution, add entry (100ml) and 1M hydrochloric acid (30ml), ethanol is heated up in a steamer in decompression.The residue that obtains is used ethyl acetate extraction after diluting with 0.1M hydrochloric acid.Organic layer cleans with saturated aqueous common salt, and behind anhydrous magnesium sulfate drying, decompression is heated up in a steamer and desolvated, and obtains the title product (7.95g) of Sandy oily matter.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.7Hz)、1.25-1.38(8H、m)、1.41-1.48(2H、m)、1.80(2H、quint、J＝7.0Hz)、2.25(1H、t、J＝6.3Hz)、3.98(2H、t、J＝6.4Hz)、4.65(2H、d、J＝6.0Hz)、6.74(1H、d、J＝8.6Hz)、7.34(1H、d?d、J＝2.4、8.6Hz)、7.41(1H、d、J＝2.4Hz)。
(35-3) synthetic (the compound 35-3) of (5-bromo-2-octyloxy benzyl) oxygen base-tertiary butyl dimethylsilane
At the N of compound 35-2 (7.95g), imidazoles (4.19g), in dinethylformamide (35ml) solution, the ice-cold TERT-BUTYL DIMETHYL CHLORO SILANE (4.45g) that adds down, ice-cold stirring down 20 minutes was at room temperature stirred 18 hours again.In reaction solution, add saturated sodium bicarbonate aqueous solution, use ethyl acetate extraction.Organic layer is with saturated sodium bicarbonate aqueous solution, then with the saturated aqueous common salt cleaning, and behind anhydrous magnesium sulfate drying, decompression is heated up in a steamer and desolvated, and obtains the title product (11.1g) of Sandy oily matter.
1H-NMR(CDCl 3)δ(ppm)：0.12(6H、s)、0.89(3H、t、J＝6.9Hz)、0.96(9H、s)、1.24-1.38(8H、m)、1.40-1.47(2H、m)、1.76(2H、quint、J＝7.0H?)、3.92(2H、t、J＝6.5Hz)、4.71(2H、s)、6.67(1H、d、J＝8.7Hz)、7.27(1H、dd、J＝2.5、8.7Hz)、7.55(1H、d、J＝2.5Hz)。
(35-4) synthetic (the compound 35-4) of { 5-[3-(t-butyldimethylsilyl oxygen ylmethyl)-4-octyloxyphenyl ethynyl]-2,2-dimethyl--1,3-diox-5-yl } carboxylamine tertiary butyl ester
In acetonitrile (150ml), add compound 35-3 (11.1g), with known method (for example tetradron the 57th rolls up (calendar year 2001) 6531-6538 page or leaf) synthetic (2; 2-dimethyl--5-ethynyl-1; 3-diox-5-yl) carboxylamine tertiary butyl ester (6.28g), 2-dicyclohexyl phosphino--2 '; 4 ', 6 '-tri isopropyl biphenyl (706mg), two (acetonitrile) palladium (II) dichloride (128mg), cesium carbonate (20.8g) stir stirring in 10 hours down at 80 ℃.Reaction solution joins in the salt solution, behind ethyl acetate extraction, cleans with saturated aqueous common salt, uses anhydrous sodium sulfate drying, and decompression is heated up in a steamer and desolvated.Residue is refining with silica gel column chromatography, obtains the title product (12.4g) of brown oil.
1H-NMR(CDCl 3)δ(ppm)：0.11(6H、s)、0.89(3H、t、J＝6.8Hz)、0.95(9H、s)、1.24-1.37(8H、m)、1.40-1.47(2H、m)、1.45(3H、s)、1.48(9H、s)、1.50(3H、s)、1.77(2H、quint、J＝6.9Hz)、3.95(2H、t、J＝6.5Hz)、4.03(2H、d、J＝11.6Hz)、4.09(2H、d、J＝11.6Hz)、4.69(2H、s)、5.19(1H、brs)、6.71(1H、d、J＝8.4Hz)、7.27(1H、dd、J＝1.9、8.4Hz)、7.49(1H、s)。
(35-5) synthetic (the compound 35-5) of { 2,2-dimethyl--5-[2-(4-octyloxy-3-hydroxymethyl phenyl) ethyl]-1,3-diox-5-yl } carboxylamine tertiary butyl ester
1, dissolved compound 35-4 (12.4g) in the 4-diox (100ml) adds 10% year palladium gac (3.0g), is stirring 5.5 hours under the atmosphere of hydrogen gas, under the room temperature.After in the nitrogen replacement reaction vessel, filtering solution, concentrated filtrate.In THF (100ml) solution of the residue that obtains, add the 1M tetrahydrofuran solution (30ml) of TBuA fluorochemical, stirred 3 hours.After reaction solution diluted with vinyl acetic monomer (200ml), water and saturated aqueous common salt cleaned, and use anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.Residue is refining with silica gel column chromatography, obtains the title product (9.61g) of filbert oily thing.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.7Hz)、1.24-1.38(8H、m)、1.41-1.47(2H、m)、1.42(3H、s)、1.43(3H、s)、1.47(9H、s)、1.79(2H、quint、J＝7.0Hz)、1.92-1.96(2H、m)、2.41(1Ht、J＝6.6Hz)、2.48-2.53(2H、m)、3.67(2H、d、J＝11.7Hz)、3.89(2H、d、J＝11.7Hz)、3.98(2H、t、J＝6.5Hz)、4.65(2H、d、J＝6.8Hz)、4.98(1H、brs)、6.77(1H、d、J＝8.0Hz)、7.04-7.07(2H、m)。
(35-6) synthetic (the compound 35-6) of { 2,2-dimethyl--5-[2-(3-methyl fluoride-4-octyloxyphenyl) ethyl]-1,3-diox-5-yl } carboxylamine tertiary butyl ester
The mixture of the 1M tetrahydrofuran solution (117ml) of compound 35-5 (9.61g), toluenesulfonyl fluoride (10.2g), molecular sieve 4A (9.61g) and TBuA fluorochemical refluxed stirred 13 hours down.Reaction solution joins in the mixed solution of water and vinyl acetic monomer, stirs 5 hours.The leaching organic layer, water, saturated aqueous common salt clean, and use anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and is desolvated.Residue is refining with silica gel column chromatography, obtains the title product (1.91g) of colorless oil.
1H-NMR(CDCl 3)δ(ppm)：0.89(3H、t、J＝6.7Hz)、1.24-1.38(8H、m)、1.40-1.47(2H、m)、1.42(3H、s)、1.43(3H、s)、1.47(9H、s)、1.77(2H、quint、J＝7.0Hz)、1.93-1.97(2H、m)、2.50-2.55(2H、m)、3.68(2H、d、J＝11.7Hz)、3.89(2H、d、J＝11.7Hz)、3.95(2H、t、J＝6.5Hz)、4.98(1H、brs)、5.42(2H、d、J＝47.9Hz)、6.78(1H、d、J＝8.4Hz)、7.11(1H、d、J＝8.4Hz)、7.17(1H、s)。
(35-7) 2-amino-2-[2-(3-methyl fluoride-4-oxygen in heptan base phenyl) ethyl] propane-1, synthetic (the compound 35-7) of 3-diol hydrochloride
Dissolved compound 35-6 (1.91g) in methyl alcohol (60ml) adds tosic acid monohydrate (20mg), at room temperature stirs 9 hours.In reaction solution, add saturated sodium bicarbonate aqueous solution (200ml) and saturated aqueous common salt (100ml), behind ethyl acetate extraction, organic layer cleans with saturated aqueous common salt, uses anhydrous sodium sulfate drying, and decompression is heated up in a steamer and desolvated.The ice-cold 4M vinyl acetic monomer solution (3ml) that adds vinyl acetic monomer (3ml) and hydrogenchloride down in the residue that obtains, ice-cold stirring down 40 minutes.The solid that leaching is separated out cleans with vinyl acetic monomer, obtains the title product (158mg) of white powder.
MS(ESI)m/z：356[M+H]
1H-NMR(DMSO-d 6)δ(ppm)：0.86(3H、t、J＝6.8Hz)、1.23-1.35(8H、m)、1.37-1.44(2H、m)、1.67-1.78(4H、m)、2.52-2.56(2H、m)、3.51(4H、d、J＝4.6Hz)、3.97(2H、t、J＝6.4Hz)、5.38(2H、d、J＝48.0Hz)、5.38(2H、brs)、6.97(1H、d、J＝8.3Hz)、7.17-7.20(2H、m)、7.75(3H、brs)。
Embodiment 36
2-dimethylamino-2-[2-(4-oxygen in heptan base-3-trifluoromethyl) ethyl] propane-1, the 3-diol hydrochloride
(36-1) 2-dimethylamino-2-[2-(4-oxygen in heptan base-3-trifluoromethyl) ethyl] propane-1, synthetic (the compound 36-1) of 3-diol hydrochloride
In acetonitrile (30ml) solution of compound 1-3 (1.24g), 37% formaldehyde (20ml), 30% aqueous acetic acid (3ml), the ice-cold cyanic acid sodium borohydride (0.817g) that adds down stirred 1 hour.After in reaction solution, adding saturated sodium bicarbonate aqueous solution (50ml), heat up in a steamer acetonitrile under the decompression.In the enriched material that obtains, add saturated sodium bicarbonate aqueous solution, behind ethyl acetate extraction, clean with saturated aqueous common salt, use anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated.The vinyl acetic monomer solution (5ml) that in residue, adds vinyl acetic monomer (10ml) and 4M hydrogenchloride, decompression is heated up in a steamer and is desolvated.In residue, add DIPE, the solid that leaching produces obtains the title product (0.808g) of white solid.
MS(ESI)m/z：406[M+H]
1H-NMR(DMSO-d 6)δ(ppm)：0.86(3H、t、J＝6.7Hz)、1.24-1.35(6H、m)、1.38-1.45(2H、m)、1.71(2H、quint、J＝6.8Hz)、1.87-1.91(2H、m)、2.60-2.67(2H、m)、2.80(6H、d、J＝4.8Hz)、3.70(2H、dd、J＝4.9、12.9Hz)、3.76(2H、dd、J＝4.8、12.8Hz)、4.06(2H、t、J＝6.2Hz)、5.71(2H、t、J＝4.6Hz)、7.18(1H、d、J＝8.2Hz)、7.49-7.51(2H、m)。
Synthetic routine 1 of comparative compound
2-amino-2-[2-(4-oxygen in heptan base-3-aminomethyl phenyl) ethyl] propane-1, the 3-diol hydrochloride
(1-1) 4 '-methoxyl group-3 '-synthetic (the comparative compound 1-1) of methyl acetophenone
4 '-hydroxyl-3 '-N of methyl acetophenone (25.0g), in dinethylformamide (120ml) solution, ice-cold salt of wormwood (69.1g) and the methyl iodide (11.4ml) of adding down, ice-cold stirring down 2 hours was at room temperature stirred 2 hours again.In water, add reaction solution, behind ethyl acetate extraction, organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated, and obtains the title product (27.5g) of yellow oil.
1H-NMR(CDCl 3)δ(ppm)：2.25(3H、s)、2.55(3H、s)、3.89(3H、s)、6.85(1H、d、J＝8.6Hz)、7.77(1H、d、J＝1.7Hz)、7.82(1H、dd、J＝2.2、8.6Hz)。
(1-2) 4 '-methoxyl group-3 '-synthetic (the comparative compound 1-2) of toluyl MB
In acetic acid (170ml) solution of comparative compound 1-1 (27.2g), add pyridine tribromide (90%, 59.0g), stirred 1 hour down at 50 ℃.In water, add reaction solution, behind ethyl acetate extraction, organic layer water, 1M aqueous sodium hydroxide solution, saturated ammonium chloride, saturated aqueous common salt successively cleans.This organic layer is used anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated, and obtains dark brown solid title product (40.3g).
1H-NMR(CDCl 3)δ(ppm)：2.26(3H、s)、3.91(3H、s)、4.40(2H、s)、6.87(1H、d、J＝8.6Hz)、7.80(1H、d、J＝1.5Hz)、7.86(1H、dd、J＝2.2、8.6Hz)。
(1-3) synthetic (the comparative compound 1-3) of 2-acetamido-2-[2-(4-methoxyl group-3-aminomethyl phenyl)-2-oxoethyl] ethyl malonate
At the N of 2-ethanamide ethyl malonate (29.1g), in dinethylformamide (140ml) solution, the ice-cold sodium hydrides (60%, 5.63g) that add for following minute four times stirred 1 hour.In this solution, add the N of comparative compound 1-2 (39.1g), dinethylformamide (50ml) solution, ice-cold stirring down 3 hours.Reaction solution joins in the frozen water, and behind ethyl acetate extraction, organic layer cleans with saturated aqueous common salt, uses anhydrous magnesium sulfate drying, and decompression is heated up in a steamer and desolvated.The residue that obtains is refining with silica gel chromatography, obtains the title product (45.0g) of dark brown oily matter.
1H-NMR(CDCl 3)δ(ppm)：1.24(6H、t、J＝7.0Hz)、1.96(3H、s)、2.23(3H、s)、3.89(3H、s)、4.20(2H、s)、4.26(4H、dq、J＝1.4、7.0Hz)、6.84(1H、d、J＝8.6Hz)、7.10(1H、brs)、7.77(1H、d、J＝1.8Hz)、7.83(1H、dd、J＝2.2、8.6Hz)。
(1-4) synthetic (the comparative compound 1-4) of 2-acetamido-2-[2-(4-methoxyl group-3-aminomethyl phenyl) ethyl] ethyl malonate
In trifluoracetic acid (260ml) solution of comparative compound 1-3 (45.0g), add triethyl silicane (133ml), stirred 24 hours down at 70 ℃.Behind the concentration of reaction solution, add entry under the decompression, use ethyl acetate extraction.Organic layer use anhydrous magnesium sulfate drying after water, 1M aqueous sodium hydroxide solution, saturated aqueous common salt clean successively, reduces pressure to heat up in a steamer and desolvates.Add diethyl ether and hexane in the residue that obtains, the solid that leaching is separated out, drying obtains the title product (31.3g) of white powder.
1H-NMR(CDCl 3)δ(ppm)：1.25(6H、t、J＝7.0Hz)、2.00(3H、s)、2.18(3H、s)、2.37-2.41(2H、m)、2.62-2.67(2H、m)、3.79(3H、s)、4.15-4.27(4H、m)、6.70-6.73(1H、m)、6.75(1H、brs)、6.90-6.93(2H、m)。
(1-5) synthetic (the comparative compound 1-5) of N-[1, two (methylol)-3-(4-methoxyl group-3-aminomethyl phenyl) propyl group of 1-] ethanamide
In the solution of the ethanol (300ml) of comparative compound 1-4 (31.3g) and water (60ml), add calcium chloride (19.0g), dissolving.In this mixed solution, ice-cold following minute five times adding Peng Qinghuanas (13.0g), ice-cold stirring down 3 hours, at room temperature 19 hours again.The ice-cold 1M hydrochloric acid (300ml) that adds down in reaction solution, after decompression concentrates down, add 0.5M hydrochloric acid (700ml) again after, use ethyl acetate extraction.Organic layer is used anhydrous magnesium sulfate drying after cleaning with saturated aqueous common salt, and decompression is heated up in a steamer and desolvated, and obtains the solid of white.In this white solid, carry out again once and above-mentioned identical operations, obtain the title product (22.8g) of colorless oil.
1H-NMR(CDCl 3)δ(ppm)：1.91-1.95(2H、m)、1.95(3H、s)、2.19(3H、s)、2.55-2.59(2H、m)、3.62(2H、d、J＝11.6Hz)、3.80(3H、s)、3.87(2H、d、J＝11.6Hz)、5.84(1H、brs)、6.74(1H、d、J＝8.8Hz)、6.97-6.98(2H、m)。
(1-6) synthetic (the comparative compound 1-6) of [1, two (methylol)-3-(the 4-hydroxy-3-methyl phenyl) propyl group of 1-] carboxylamine tertiary butyl ester
In methylene dichloride (200ml) solution of comparative compound 1-5 (22.5g), at-70 ℃ of 1M dichloromethane solutions (320ml) that drip boron tribromide down.Stir on the limit, and the limit was warmed up to 0 ℃ with 1 and a half hours, stirred 1 and a half hours down ice-cold again.In reaction solution ice-cold down slowly add methyl alcohol (300ml) after, decompression concentrates down.In ethanol (100ml) solution of the residue that obtains, add concentrated hydrochloric acid (100ml), stirred 4 hours down at 80 ℃.Concentration of reaction solution under reducing pressure, at residue that obtains and N, in methyl alcohol (150ml) solution of N-diisopropylethylamine (34.8ml), the ice-cold di-tert-butyl dicarbonic acid ester (19.2g) that adds down, ice-cold stirring down 1 hour was at room temperature stirred 4 hours again.Behind the concentration of reaction solution, add saturated sodium bicarbonate aqueous solution (500ml) under the decompression, use ethyl acetate extraction.Organic layer cleans with saturated sodium bicarbonate aqueous solution, saturated aqueous common salt successively, and behind anhydrous magnesium sulfate drying, decompression is heated up in a steamer and desolvated.The residue that obtains cleans with diethyl ether, obtains the title product (15.1g) of white powder.
1H-NMR(CDCl 3)δ(ppm)：1.45(9H、s)、1.82-1.86(2H、m)、2.21(3H、s)、2.50-2.54(2H、m)、3.39(2H、brs)、3.64(2H、dd、J＝6.8、11.5Hz)、3.88(2H、dd、J＝5.5、11.5Hz)、4.83(1H、brs)、4.99(1H、brs)、6.68(1H、d、J＝8.1Hz)、6.88(1H、dd、J＝1.9、8.1Hz)、6.94(1H、d、J＝1.9Hz)。
(1-7) 2-amino-2-[2-(4-oxygen in heptan base-3-aminomethyl phenyl) ethyl] propane-1, synthetic (the comparative compound 1-7) of 3-diol hydrochloride
At N, dissolving comparative compound 1-6 (500mg) adds salt of wormwood (425mg), n-heptyl bromide (0.296ml) in the dinethylformamide (10ml), stirs 6 hours down at 80 ℃.Add entry in the reaction solution, behind ethyl acetate extraction, in water, saturated aqueous common salt, clean, use anhydrous magnesium sulfate drying, decompression is heated up in a steamer and is desolvated, and obtains the 640mg colorless oil.This colorless oil (640mg) is dissolved in the methylene dichloride (5ml), adds and contains hydrogenchloride De diox (4mol/l, 5ml), at room temperature stirs 15 hours.Concentration of reaction solution, residue cleans with diethyl ether, obtains white powder.With refining this white powder of preparation HPLC, add the ether (1mol/l, 15ml) that contains hydrogenchloride in the residue that obtains, process hydrochloride after, the leaching precipitate, drying obtains the title product (320mg) of white powder.
MS(ESI)m/z：324[M+H]
1H-NMR(CD 3OD)δ(ppm)：0.91(3H、t、J＝6.6Hz)、1.30-1.42(6H、m)、1.43-1.52(2H、m)、1.74-1.81(2H、m)、1.88-1.94(2H、m)、2.16(3H、s)、2.53-2.58(2H、m)、3.64-3.71(4H、m)、3.94(2H、t、J＝6.4Hz)、6.77(1H、d、J＝8.0Hz)、6.96-6.98(2H、m)。
The structure of synthetic compound is represented as follows.
[Chemical formula 2 3]
Figure S2006800472557D01131
[Chemical formula 2 4]
[Chemical formula 2 5]
Figure S2006800472557D01151
[Chemical formula 2 6]
Figure S2006800472557D01161
[Chemical formula 2 7]
Figure S2006800472557D01171
[Chemical formula 2 8]
Figure S2006800472557D01181
[Chemical formula 2 9]
Figure S2006800472557D01191
[chemical formula 30]
Figure S2006800472557D01201
[chemical formula 31]
Figure S2006800472557D01211
Experimental example 1: the mouse peripheral blood lymphocyte is counted the evaluation of minimizing effect
The compounds of this invention is dissolved or suspended in 20% Schardinger dextrins (manufacturing of japanese food chemical company), with the consumption of 0.001～10mg/kg body weight, the intraperitoneal of the male BALB/cAnNCrj mouse (Japanese チ ヤ one Le ス リ バ one) of offeing medicine for 7～10 ages in week.Administration compound of the present invention is after 24 hours, and from the back vena cava of mouse, the tuberculin that uses heparin sodium (ノ ボ ノ Le デ イ ス Network manufactured) processing is taked about 0.3ml tip blood with syringe (テ Le モ manufactured) under etherization.After using the blood haemolysis of automatic haemolysis treatment unit (TQ-Prep, ベ Star Network マ Application コ one Le タ one manufactured) with 0.1ml; Using flow cytometer (CYTOMICS FC 500, ベ Star Network マ Application コ one Le タ one manufactured), is Flow-Count with the standard particle of known number TMFluorospheres (ベ Star Network マ Application コ one Le タ one manufactured) is as internal standard, as index, measures lymphocyte quantity with gating (gating) method with the place ahead of laser and side scattering.Carrier crowd's lymphocyte number as 100% o'clock, is calculated it and reduces by 50% consumption, as ED 50Value (mg/kg body weight).The mouse peripheral blood lymphocyte of comparative compound 1-7 is counted the minimizing effect and is used ED 50The value meter, with respect to the 0.64mg/kg body weight, the mouse peripheral blood lymphocyte of compound 1-3, compound 13-6, compound 15-3, compound 28-6 is counted the minimizing effect and is used ED 50Value meter is respectively 0.04,0.02,0.02, the 0.03mg/kg body weight.
Experimental example 2: in the mouse remote measurement to the effect of palmic rate
Male Sprague-Dawley (IGS) mouse is dropped into vetanarcol (big Japanese drugmaker makes) at intraperitoneal; After the anesthesia; In abdominal aorta, insert the pressure inductor be connected on the telemetry transmitter (TL11M2-C50-PTX, digital science international corporation make), keep somewhere projector in subcutaneous abdomen.The data of blood pressure palmic rate through receptor (RPC-1, digital science international corporation make) by analysis software (Dataquest A.R.T., digital scientific company) record.Operation back from 10 days to through behind 2 time-of-weeks, confirm that the diel rhythm of palmic rate has been replied, be provided in the experiment.The compounds of this invention is suspended in 0.5% HYDROXY PROPYL METHYLCELLULOSE (SHIN-ETSU HANTOTAI's chemical industry is made), the oral administration administration.Palmic rate was measured after from preceding 24 hours of administration to administration in 72 hours.Compound 1-3 is with dosage 30mg/kg body weight, to the not influence of palmic rate of mouse.
Experimental example 3: the effect to the palmic rate of mouse is descended in anesthesia
To male Sprague-Dawley (IGS) mouse intraperitoneal administration vetanarcol (big SUMITOMO CHEMICAL drugmaker make), after the anesthesia, in back fixation.Installing electrodes on four limbs is used electrocardiogram amplifier (AC-601G, Japanese photoelectricity manufactured), measures electrocardiogram(ECG according to standard four limbs II revulsion.Electrocardiagraphic wave is measured palmic rate as triggering device through instantaneous palmic rate meter unit (AT-601G, Japanese photoelectricity manufactured).Tested compound dissolution in 20% Schardinger dextrins (manufacturing of japanese food chemical company),, be administered into intravenously through 30 seconds with the consumption of 0.001～10mg/kg body weight.When being 1,2,3,4,5,10 and 15 minute before administration, after the administration, palmic rate measures.
Result according to above-mentioned experimental example 1; The compounds of this invention is because have good peripheral blood lymphocyte minimizing effect; Can expect that it shows good immunosuppressive action, rejection restraining effect, anaphylaxis restraining effect, think treatment or prevention for auto-immune disease; The prevention of opposing that produces in the transplanting of organ or tissue or acute rejection or chronic rejection or inhibition; Transplant treatment or the prevention sick in bone marrow transplantation to host (GvH); Allergic disorder treatment or prevention are effective.And then, according to the result of above-mentioned experimental example 2, think that The compounds of this invention is to have the compound that alleviates spinoffs such as bradyrhythmia.
The application is that the spy with japanese publication is willing to what 2005-361363 was the basis, and its content is all introduced in this specification sheets.

Claims (15)

1. a compound or its pharmaceutically useful acid salt, it is with shown in the formula (I),
Figure FSB00000788436300011
In the formula, R is a Wasserstoffatoms, and X is Sauerstoffatom or sulphur atom, and Y is CH 2CH 2Or CH=CH, R 1Be trifluoromethyl, R 2Be can be by hydroxyl substituted or can be 1～4 alkyl by the substituted carbonatoms of halogen atom, R 3And R 4Be Wasserstoffatoms, n representes 5～8.
2. like compound or its pharmaceutically useful acid salt of record in the claim 1, it is a formula (Ia) or (Ib)
Figure FSB00000788436300012
In the formula, R is a Wasserstoffatoms, and X is Sauerstoffatom or sulphur atom, R 1Be trifluoromethyl, R 2Be to replace or be 1～4 alkyl by the substituted carbonatoms of halogen atom by hydroxyl.
3. like compound or its pharmaceutically useful acid salt of record in the claim 1, wherein, X is a Sauerstoffatom.
4. like compound or its pharmaceutically useful acid salt of record in the claim 1, wherein, Y is CH 2CH 2
As in the claim 1 record compound or its pharmaceutically useful acid salt, wherein, R 2Be methyl or methylol.
As in the claim 1 record compound or its pharmaceutically useful acid salt, wherein, R 2It is methylol.
7. like compound or its pharmaceutically useful acid salt of record in the claim 2, it is formula (Ia)
Figure FSB00000788436300013
As in the claim 7 record compound or its pharmaceutically useful acid salt, wherein, R 2It is methylol.
9. like compound or its pharmaceutically useful acid salt of record in the claim 8, wherein, X is a Sauerstoffatom.
10. like compound or its pharmaceutically useful acid salt of record in the claim 1, wherein, the compound of general formula (I) is any among following a～d,
A.2-amino-2-[2-(4-oxygen in heptan base-3-trifluoromethyl) ethyl] propane-1,3-glycol or its pharmaceutically useful acid salt
B. (E)-2-amino-2-[2-(4-oxygen in heptan base-3-trifluoromethyl) vinyl] propane-1,3-glycol or its pharmaceutically useful acid salt
C.2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-methyl butanol or its pharmaceutically useful acid salt
D. (R)-2-amino-4-(4-oxygen in heptan base-3-trifluoromethyl)-2-methyl butanol or its pharmaceutically useful acid salt.
11.2-amino-2-[2-(4-oxygen in heptan base-3-trifluoromethyl) ethyl] propane-1, the hydrochloride of 3-glycol.
12. a medical composition contains one of any compound and pharmaceutically useful carrier in the claim 1～11.
13. in the claim 1～11 one of any compound of record or its pharmaceutically useful acid salt preparation from the therapeutical agent of immunological disease or preventive, to the preventive of the opposing in the transplanting of organ or tissue or acute rejection or chronic rejection or suppressor factor, by the transplant of bone marrow transplantation to the therapeutical agent of versus-host disease or the application in preventive, allergic disorder therapeutical agent or the preventive.
14., be rheumatic arthritis, multiple sclerosis, encephalomyelitis, systemic lupus erythematosus, systemic lupus erythematosus, nephrotic syndrome, chronic eczema, type i diabetes from immunological disease like the application of record in the claim 13.
15. like the application of record in the claim 13, allergic disorder is specific reaction atopic dermatitis, allergic rhinitis, asthma.
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